Phenylaminopropanol Derivatives and Methods of Their Use

ABSTRACT

The present invention is directed to phenylaminopropanol derivatives of formula I: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof, compositions containing these derivatives, and methods of their use for the prevention and treatment of conditions ameliorated by monoamine reuptake including, inter alia, vasomotor symptoms (VMS), sexual dysfunction, gastrointestinal and genitourinary disorders, chronic fatigue syndrome, fibromyalgia syndrome, nervous system disorders, and combinations thereof, particularly those conditions selected from the group consisting of major depressive disorder, vasomotor symptoms, stress and urge urinary incontinence, fibromyalgia, pain, diabetic neuropathy, and combinations thereof.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Application No. 60/557,831filed Mar. 30, 2004 and U.S. Application No. 60/569,861 filed May 11,2004, the entire disclosures of which are herein incorporated byreference.

FIELD OF THE INVENTION

The present invention relates to phenylaminopropanol derivatives,compositions containing these derivatives, and methods of their use forthe prevention and treatment of conditions ameliorated by monoaminereuptake including, inter alia, vasomotor symptoms (VMS), sexualdysfunction, gastrointestinal and genitourinary disorders, chronicfatigue syndrome, fibromyalgia syndrome, nervous system disorders, andcombinations thereof, particularly those conditions selected from thegroup consisting of major depressive disorder, vasomotor symptoms,stress and urge urinary incontinence, fibromyalgia, pain, diabeticneuropathy, and combinations thereof.

BACKGROUND OF THE INVENTION

Vasomotor symptoms (VMS), referred to as hot flushes and night sweats,are the most common symptoms associated with menopause, occurring in 60%to 80% of all women following natural or surgically-induced menopause.VMS are likely to be an adaptive response of the central nervous system(CNS) to declining sex steroids. To date, the most effective therapiesfor VMS are hormone-based treatments, including estrogens and/or someprogestins. Hormonal treatments are very effective at alleviating VMS,but they are not appropriate for all women. It is well recognized thatVMS are caused by fluctuations of sex steroid levels and can bedisruptive and disabling in both males and females. A hot flush can lastup to thirty minutes and vary in their frequency from several times aweek to multiple occurrences per day. The patient experiences a hotflash as a sudden feeling of heat that spreads quickly from the face tothe chest and back and then over the rest of the body. It is usuallyaccompanied by outbreaks of profuse sweating. It may sometimes occurseveral times an hour, and it often occurs at night. Hot flushes andoutbreaks of sweats occurring during the night can cause sleepdeprivation. Psychological and emotional symptoms observed, such asnervousness, fatigue, irritability, insomnia, depression, memory loss,headache, anxiety, nervousness or inability to concentrate areconsidered to be caused by the sleep deprivation following hot flush andnight sweats (Kramer et al., In: Murphy et al., 3^(rd) Int'l Symposiumon Recent Advances in Urological Cancer Diagnosis andTreatment-Proceedings, Paris, France: SCI: 3-7 (1992)).

Hot flushes may be even more severe in women treated for breast cancerfor several reasons: 1) many survivors of breast cancer are giventamoxifen, the most prevalent side effect of which is hot flush, 2) manywomen treated for breast cancer undergo premature menopause fromchemotherapy, 3) women with a history of breast cancer have generallybeen denied estrogen therapy because of concerns about potentialrecurrence of breast cancer (Loprinzi, et al., Lancet, 2000, 356(9247):2059-2063).

Men also experience hot flushes following steroid hormone (androgen)withdrawal. This is true in cases of age-associated androgen decline(Katovich, et al., Proceedings of the Society for Experimental Biology &Medicine, 1990, 193(2): 129-35) as well as in extreme cases of hormonedeprivation associated with treatments for prostate cancer (Berendsen,et al., European Journal of Pharmacology, 2001, 419(1): 47-54. As manyas one-third of these patients will experience persistent and frequentsymptoms severe enough to cause significant discomfort andinconvenience.

The precise mechanism of these symptoms is unknown but generally isthought to represent disturbances to normal homeostatic mechanismscontrolling thermoregulation and vasomotor activity (Kronenberg et al.,“Thermoregulatory Physiology of Menopausal Hot Flashes: A Review,” Can.J. Physiol. Pharmacol., 1987, 65:1312-1324).

The fact that estrogen treatment (e.g. estrogen replacement therapy)relieves the symptoms establishes the link between these symptoms and anestrogen deficiency. For example, the menopausal stage of life isassociated with a wide range of other acute symptoms as described aboveand these symptoms are generally estrogen responsive.

It has been suggested that estrogens may stimulate the activity of boththe norepinephrine (NE) and/or serotonin (5-HT) systems (J. Pharmacology& Experimental Therapeutics, 1986, 236(3) 646-652). It is hypothesizedthat estrogens modulate NE and 5-HT levels providing homeostasis in thethermoregulatory center of the hypothalamus. The descending pathwaysfrom the hypothalamus via brainstem/spinal cord and the adrenals to theskin are involved in maintaining normal skin temperature. The action ofNE and 5-HT reuptake inhibitors is known to impinge on both the CNS andperipheral nervous system (PNS). The pathophysiology of VMS is mediatedby both central and peripheral mechanisms and, therefore, the interplaybetween the CNS and PNS may account for the efficacy of dual actingSRI/NRIs in the treatment of thermoregulatory dysfunction. In fact, thephysiological aspects and the CNS/PNS involvement in VMS may account forthe lower doses proposed to treat VMS (Loprinzi, et al., Lancet, 2000,356:2059-2063; Stearns et al., JAMA, 2003, 289:2827-2834) compared todoses used to treat the behavioral aspects of depression. The interplayof the CNS/PNS in the pathophysiology of VMS and the presented datawithin this document were used to support the claims that thenorepinephrine system could be targeted to treat VMS.

Although VMS are most commonly treated by hormone therapy (orally,transdermally, or via an implant), some patients cannot tolerateestrogen treatment (Berendsen, Maturitas, 2000, 36(3): 155-164, Fink etal., Nature, 1996, 383(6598): 306). In addition, hormone replacementtherapy is usually not recommended for women or men with or at risk forhormonally sensitive cancers (e.g. breast or prostate cancer). Thus,non-hormonal therapies (e.g. fluoxetine, paroxetine [SRIs] andclonidine) are being evaluated clinically. WO9944601 discloses a methodfor decreasing hot flushes in a human female by administeringfluoxetine. Other options have been studied for the treatment of hotflashes, including steroids, alpha-adrenergic agonists, andbeta-blockers, with varying degree of success (Waldinger et al.,Maturitas, 2000, 36(3): 165-168).

It has been reported that α₂-adrenergic receptors play a role inthermoregulatory dysfunctions (Freedman et al., Fertility & Sterility,2000, 74(1): 20-3). These receptors are located both pre- andpost-synaptically and mediate an inhibitory role in the central andperipheral nervous system. There are four distinct subtypes of theadrenergic_(α2) receptors, i.e., are α_(2A), α_(2B), α_(2C) and α_(2D)(Mackinnon et al., TIPS, 1994, 15: 119; French, Pharmacol. Ther., 1995,68: 175). It has been reported that a non-select α₂-adrenoceptorantagonist, yohimbine, induces a flush and an α₂-adrenergic receptoragonist, clonidine, alleviates the yohimbine effect (Katovich, et al.,Proceedings of the Society for Experimental Biology & Medicine, 1990,193(2): 129-35, Freedman et al., Fertility & Sterility, 2000, 74(1):20-3). Clonidine has been used to treat hot flush. However, using suchtreatment is associated with a number of undesired side effects causedby high doses necessary to abate hot flash described herein and known inthe related arts.

Given the complex multifaceted nature of thermoregulation and theinterplay between the CNS and PNS in maintaining thermoregulatoryhomeostasis, multiple therapies and approaches can be developed totarget vasomotor symptoms. The present invention focuses on novelcompounds and compositions containing these compounds directed to theseand other important uses.

SUMMARY OF THE INVENTION

The present invention is directed to phenylaminopropanol derivatives,compositions containing these derivatives, and methods of their use forthe prevention and treatment of conditions ameliorated by monoaminereuptake including, inter alia, vasomotor symptoms (VMS), sexualdysfunction, gastrointestinal and genitourinary disorders, chronicfatigue syndrome, fibromyalgia syndrome, nervous system disorders, andcombinations thereof, particularly those conditions selected from thegroup consisting of major depressive disorder, vasomotor symptoms,stress and urge urinary incontinence, fibromyalgia, pain, diabeticneuropathy, and combinations thereof.

In one embodiment, the invention is directed to compounds of formula I:

or a pharmaceutically acceptable salt thereof;

wherein:

the dotted line represents an optional double bond between U and V or Vand W;

U is, independently, O, S, SO, SO₂, C═O, N, NR₃, or C(R₈)₂;

W is CH, CH₂, or C═O;

provided that when W is CH₂, U is not C(R₈)₂;

V is C(R₈), C(R₈)₂, O, or N(R₈);

R₁ is, independently at each occurrence, alkyl, alkoxy, halo, CF₃, OCF₃,arylalkyloxy substituted with 0-3 R₉, aryloxy substituted with 0-3 R₉,aryl substituted with 0-3 R₉, heteroaryl substituted with 0-3 R₉,hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, alkynyl, alkylsulfoxide,phenylsulfoxide substituted with 0-3 R₉, alkylsulfone, phenylsulfonesubstituted with 0-3 R₉, alkylsulfonamide, phenylsulfonamide substitutedwith 0-3 R₉, heteroaryloxy substituted with 0-3 R₉, heteroarylmethyloxysubstituted with 0-3 R₉, alkylamido, or phenylamido substituted with 0-3R₉; or two adjacent R₁ also represent methylenedioxy;

R₂ is aryl substituted with 0-3 R₁ or heteroaryl substituted with 0-3R₁;

R₃ is H, C₁-C₄ alkyl substituted with 0-3 R₁, C₃-C₆ cycloalkyl, orphenyl substituted with 0-3 R₁;

R₄ is, independently at each occurrence, H, C₁-C₄ alkyl, arylalkyl,heteroarylmethyl, cycloheptylmethyl, cyclohexylmethyl,cyclopentylmethyl, or cyclobutylmethyl, or

both R₄ groups, together with the nitrogen through which they areattached, form a heterocyclic ring of 4 to 6 ring atoms, where onecarbon may be optionally replaced with N, O, S, or SO₂, and where anycarbon ring atom or additional N atom may be optionally substituted withC₁-C₄ alkyl, F, or CF₃;

R₅ is H or C₁-C₄ alkyl;

R₆ is H or C₁-C₄ alkyl;

R₇ is, independently at each occurrence, H, or C₁-C₄ alkyl, or

R₇ and R₄ together with the nitrogen to which R₄ is attached form anitrogen-containing ring containing 3-6 carbon atoms;

R₈ is, independently at each occurrence, H, C₁-C₄ alkyl, C₃-C₆heteroalkyl, or aryl substituted with 0-3 R₁;

R₉ is, independently at each occurrence, alkyl, alkoxy, halo, CF₃, OCF₃,hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, alkynyl, alkylsulfoxide,alkylsulfone, alkylsulfonamide, or alkylamido; or two adjacent R₉ alsorepresent methylenedioxy;

n is an integer from 0 to 4;

x is an integer from 1 to 2; and

wherein 1-3 carbon atoms in ring A may optionally be replaced with N.

In yet other embodiments, the present invention is directed tocompositions, comprising:

a. at least one compound of formula I; andb. at least one pharmaceutically acceptable carrier.

In another embodiment, the present invention is directed to methods fortreating or preventing a condition ameliorated by monoamine reuptake ina subject in need thereof, comprising the step of:

administering to said subject an effective amount of a compound offormula I or pharmaceutically acceptable salt thereof.

The conditions ameliorated by monoamine reuptake include those selectedfrom the group consisting of vasomotor symptoms, sexual dysfunction,gastrointestinal and genitourinary disorders, chronic fatigue syndrome,fibromyalgia syndrome, nervous system disorders, and combinationsthereof, particularly those conditions selected from the groupconsisting of major depressive disorder, vasomotor symptoms, stress andurge urinary incontinence, fibromyalgia, pain, diabetic neuropathy, andcombinations thereof.

In another embodiment, the present invention is directed to methods fortreating or preventing vasomotor symptoms in a subject in need thereof,comprising the step of:

administering to said subject an effective amount of at least onecompound of formula I or pharmaceutically acceptable salt thereof.

In yet another embodiment, the present invention is directed to methodsfor treating or preventing a depression disorder in a subject in needthereof, comprising the step of:

administering to said subject an effective amount of at least onecompound of formula I or pharmaceutically acceptable salt thereof.

In yet other embodiments, the present invention is directed to methodsfor treating or preventing sexual dysfunction in a subject in needthereof, comprising the step of:

administering to said subject an effective amount of at least onecompound of formula I or pharmaceutically acceptable salt thereof.

In further embodiments, the present invention is directed to methods fortreating or preventing pain in a subject in need thereof, comprising thestep of:

administering to said subject an effective amount of at least onecompound of formula I or pharmaceutically acceptable salt thereof.

In another embodiment, the present invention is directed to methods fortreating or preventing gastrointestinal or genitourinary disorder,particularly stress incontinence or urge urinary incontinence, in asubject in need thereof, comprising the step of:

administering to said subject an effective amount of at least onecompound of formula I or pharmaceutically acceptable salt thereof.

In another embodiment, the present invention is directed to methods fortreating or preventing chronic fatigue syndrome in a subject in needthereof, comprising the step of:

administering to said subject an effective amount of at least onecompound of formula I or pharmaceutically acceptable salt thereof.

In another embodiment, the present invention is directed to methods fortreating or preventing fibromyalgia syndrome in a subject in needthereof, comprising the step of:

administering to said subject an effective amount of at least onecompound of formula I or pharmaceutically acceptable salt thereof.

BRIEF DESCRIPTION OF THE DRAWINGS

The invention can be more fully understood from the following detaileddescription and the accompanying drawings that form a part of thisapplication.

FIG. 1 is an overview of estrogen action on norepinephrine/serotoninmediated thermoregulation.

FIG. 2 is a schematic representation of the interactions ofnorepinephrine and serotonin and their respective receptors (5-HT_(2a),α₁ and α₂-adrenergic).

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to phenylaminopropanol derivatives,compositions containing these derivatives, and methods of their use forthe prevention and treatment of conditions ameliorated by monoaminereuptake including, inter alia, vasomotor symptoms (VMS), sexualdysfunction, gastrointestinal and genitourinary disorders, chronicfatigue syndrome, fibromyalgia syndrome, nervous system disorders, andcombinations thereof, particularly those conditions selected from thegroup consisting of major depressive disorder, vasomotor symptoms,stress and urge urinary incontinence, fibromyalgia, pain, diabeticneuropathy, and combinations thereof.

The following definitions are provided for the full understanding ofterms and abbreviations used in this specification.

As used herein and in the appended claims, the singular forms “a,” “an,”and “the” include the plural reference unless the context clearlyindicates otherwise. Thus, for example, a reference to “an antagonist”includes a plurality of such antagonists, and a reference to “acompound” is a reference to one or more compounds and equivalentsthereof known to those skilled in the art, and so forth.

The abbreviations in the specification correspond to units of measure,techniques, properties, or compounds as follows: “min” means minutes,“h” means hour(s), “μL” means microliter(s), “mL” means milliliter(s),“mM” means millimolar, “M” means molar, “mmole” means millimole(s), “cm”means centimeters, “SEM” means standard error of the mean and “IU” meansInternational Units. “Δ° C.” and Δ “ED₅₀ value” means dose which resultsin 50% alleviation of the observed condition or effect (50% mean maximumendpoint).

“Norepinephrine transporter” is abbreviated NET.

“Human norepinephrine transporter” is abbreviated hNET.

“Serotonin transporter” is abbreviated SERT.

“Human serotonin transporter” is abbreviated hSERT.

“Norepinephrine reuptake inhibitor” is abbreviated NRI.

“Selective norepinephrine reuptake inhibitor” is abbreviated SNRI.

“Serotonin reuptake inhibitor” is abbreviated SRI.

“Selective serotonin reuptake inhibitor” is abbreviated SSRI.

“Norepinephrine” is abbreviated NE.

“Serotonin is abbreviated 5-HT.

“Subcutaneous” is abbreviated sc.

“Intraperitoneal” is abbreviated ip.

“Oral” is abbreviated po.

In the context of this disclosure, a number of terms shall be utilized.The term “treatment” as used herein includes preventative (e.g.,prophylactic), curative or palliative treatment and “treating” as usedherein also includes preventative, curative and palliative treatment.

The term “effective amount,” as used herein, refers to an amounteffective, at dosages, and for periods of time necessary, to achieve thedesired result with respect to prevention or treatment of vasomotorsymptoms, depression disorders, sexual dysfunction, or pain. Inparticular, with respect to vasomotor symptoms, “effective amount”refers to the amount of compound or composition of compounds that wouldincrease norepinephrine levels to compensate in part or total for thelack of steroid availability in subjects subject afflicted with avasomotor symptom. Varying hormone levels will influence the amount ofcompound required in the present invention. For example, thepre-menopausal state may require a lower level of compound due to higherhormone levels than the peri-menopausal state.

It will be appreciated that the effective amount of components of thepresent invention will vary from patient to patient not only with theparticular compound, component or composition selected, the route ofadministration, and the ability of the components (alone or incombination with one or more combination drugs) to elicit a desiredresponse in the individual, but also with factors such as the diseasestate or severity of the condition to be alleviated, hormone levels,age, sex, weight of the individual, the state of being of the patient,and the severity of the pathological condition being treated, concurrentmedication or special diets then being followed by the particularpatient, and other factors which those skilled in the art willrecognize, with the appropriate dosage ultimately being at thediscretion of the attendant physician. Dosage regimens may be adjustedto provide the improved therapeutic response. An effective amount isalso one in which any toxic or detrimental effects of the components areoutweighed by the therapeutically beneficial effects.

Preferably, the compounds of the present invention are administered at adosage and for a time such that the number of hot flushes is reduced ascompared to the number of hot flushes prior to the start of treatment.Such treatment can also be beneficial to reduce the overall severity orintensity distribution of any hot flushes still experienced, as comparedto the severity of hot flushes prior to the start of the treatment. Withrespect to depression disorders, sexual dysfunction, and pain, thecompounds of the present invention are administered at a dosage and fora time such that there is the prevention, alleviation, or elimination ofthe symptom or condition.

For example, for an afflicted patient, compounds of formula I, or apharmaceutically acceptable salt thereof, may be administered,preferably, at a dosage of from about 0.1 mg/day to about 500 mg/day,dosed one or two times daily, more preferably from about 1 mg/day toabout 200 mg/day and most preferably from about 1 mg/day to 100 mg/dayfor a time sufficient to reduce and/or substantially eliminate thenumber and/or severity of hot flushes or symptom or condition of thedepression disorder, sexual dysfunction, or pain.

The terms “component,” “composition of compounds,” “compound,” “drug,”or “pharmacologically active agent” or “active agent” or “medicament”are used interchangeably herein to refer to a compound or compounds orcomposition of matter which, when administered to a subject (human oranimal) induces a desired pharmacological and/or physiologic effect bylocal and/or systemic action.

The terms “component”, “drug” or “pharmacologically active agent” or“active agent” or “medicament” are used interchangeably herein to referto a compound or compounds or composition of matter which, whenadministered to an organism (human or animal) induces a desiredpharmacologic and/or physiologic effect by local and/or systemic action.

The term “modulation” refers to the capacity to either enhance orinhibit a functional property of a biological activity or process, forexample, receptor binding or signaling activity. Such enhancement orinhibition may be contingent on the occurrence of a specific event, suchas activation of a signal transduction pathway and/or may be manifestonly in particular cell types. The modulator is intended to comprise anycompound, e.g., antibody, small molecule, peptide, oligopeptide,polypeptide, or protein, preferably small molecule, or peptide.

As used herein, the term “inhibitor” refers to any agent that inhibits,suppresses, represses, or decreases a specific activity, such asserotonin reuptake activity or the norepinephrine reuptake activity.

The term “inhibitor” is intended to comprise any compound, e.g.,antibody, small molecule, peptide, oligopeptide, polypeptide, orprotein, preferably small molecule or peptide, that exhibits a partial,complete, competitive and/or inhibitory effect on mammalian, preferablythe human norepinephrine reuptake or both serotonin reuptake and thenorepinephrine reuptake, thus diminishing or blocking, preferablydiminishing, some or all of the biological effects of endogenousnorepinephrine reuptake or of both serotonin reuptake and thenorepinephrine reuptake.

Within the present invention, the compounds of formula I may be preparedin the form of pharmaceutically acceptable salts. As used herein, theterm “pharmaceutically acceptable salts” refers to salts prepared frompharmaceutically acceptable non-toxic acids, including inorganic salts,and organic salts. Suitable non-organic salts include inorganic andorganic acids such as acetic, benzenesulfonic, benzoic, camphorsulfonic,citric, ethenesulfonic, fumaric, gluconic, glutamic, hydrobromic,hydrochloric, isethionic, lactic, malic, maleic, mandelic,methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric,succinic, sulfuric, tartaric acid, p-toluenesulfonic and the like.Particularly preferred are hydrochloric, hydrobromic, phosphoric, andsulfuric acids, and most preferably is the hydrochloride salt.

“Administering,” as used herein, means either directly administering acompound or composition of the present invention, or administering aprodrug, derivative or analog which will form an equivalent amount ofthe active compound or substance within the body.

The term “subject” or “patient” refers to an animal including the humanspecies that is treatable with the compositions, and/or methods of thepresent invention. The term “subject” or “subjects” is intended to referto both the male and female gender unless one gender is specificallyindicated. Accordingly, the term “patient” comprises any mammal whichmay benefit from treatment or prevention of vasomotor symptoms,depression disorders, sexual dysfunction, or pain, such as a human,especially if the mammal is female, either in the pre-menopausal,peri-menopausal, or post-menopausal period. Furthermore, the termpatient includes female animals including humans and, among humans, notonly women of advanced age who have passed through menopause but alsowomen who have undergone hysterectomy or for some other reason havesuppressed estrogen production, such as those who have undergonelong-term administration of corticosteroids, suffer from Cushing'ssyndrome or have gonadal dysgenesis. However, the term “patient” is notintended to be limited to a woman.

The terms “premature menopause” or “artificial menopause” refer toovarian failure of unknown cause that may occur before age 40. It may beassociated with smoking, living at high altitude, or poor nutritionalstatus. Artificial menopause may result from oophorectomy, chemotherapy,radiation of the pelvis, or any process that impairs ovarian bloodsupply.

The term “pre-menopausal” means before the menopause, the term“peri-menopausal” means during the menopause and the term“post-menopausal” means after the menopause. “Ovariectomy” means removalof an ovary or ovaries and can be effected according to Merchenthaler etal., Maturitas, 1998, 30(3): 307-316.

“Side effect” refers to a consequence other than the one(s) for which anagent or measure is used, as the adverse effects produced by a drug,especially on a tissue or organ system other then the one sought to bebenefited by its administration. In the case, for example, of high dosesof NRIs or NRI/SRI compounds alone, the term “side effect” may refer tosuch conditions as, for example, vomiting, nausea, sweating, and flushes(Janowsky, et al., Journal of Clinical Psychiatry, 1984, 45(10 Pt 2):3-9).

“Alkyl,” as used herein, refers to an optionally substituted, saturatedstraight, branched, or cyclic hydrocarbon having from about 1 to about20 carbon atoms (and all combinations and subcombinations of ranges andspecific numbers of carbon atoms therein), with from about 1 to about 8carbon atoms being preferred, and with from about 1 to about 4 carbonatoms, herein referred to as “lower alkyl”, being more preferred. Alkylgroups include, but are not limited to, methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, cyclopentyl, isopentyl,neopentyl, n-hexyl, isohexyl, cyclohexyl, cyclooctyl, adamantyl,3-methylpentyl, 2,2-dimethylbutyl, and 2,3-dimethylbutyl.

“Heteroalkyl,” as used herein, refers to a substituent of the generalformula (alkyl-X)_(n)-alkyl-, where each “alkyl” is independently asdefined above, “X” is a sulfur, oxygen, or N heteroatom-containingmoiety, and n is 1-4, preferably one. Heteroalkyl groups include, butare not limited to, methoxymethyl, ethoxyethyl, methoxyethyl,methylsulfanylmethyl, ethylsulfanylethyl, methylsulfanylethyl,methylaminoethyl, ethylaminoethyl, and methylaminoethyl.

“Perfluorinated alkyl,” as used herein, refers to an alkyl, as definedabove, in which the hydrogens directly attached to the carbon atoms arecompletely replaced by fluorine.

“Alkenyl,” as used herein, refers to an alkyl group of at least twocarbon atoms having one or more double bonds, wherein alkyl is asdefined herein. Alkenyl groups can be optionally substituted.

“Alkynyl,” as used herein, refers to an alkyl group of at least twocarbon atoms having one or more triple bonds, wherein alkyl is asdefined herein. Alkynyl groups can be optionally substituted.

“Aryl” as used herein, refers to an optionally substituted, mono-, di-,tri-, or other multicyclic aromatic ring system having from about 5 toabout 50 carbon atoms (and all combinations and subcombinations ofranges and specific numbers of carbon atoms therein), with from about 6to about 10 carbons being preferred. Non-limiting examples include, forexample, phenyl, naphthyl, anthracenyl, and phenanthrenyl.

“Heteroaryl,” as used herein, refers to an optionally substituted,mono-, di-, tri-, or other multicyclic aromatic ring system thatincludes at least one, and preferably from 1 to about 4 heteroatom ringmembers selected from sulfur, oxygen and nitrogen. Heteroaryl groups canhave, for example, from about 3 to about 50 carbon atoms (and allcombinations and subcombinations of ranges and specific numbers ofcarbon atoms therein), with from about 4 to about 10 carbons beingpreferred. Non-limiting examples of heteroaryl groups include, forexample, pyrryl, furyl, pyridyl, 1,2,4-thiadiazolyl, pyrimidyl, thienyl,isothiazolyl, imidazolyl, tetrazolyl, pyrazinyl, pyrimidyl, quinolyl,isoquinolyl, thiophenyl, benzothienyl, isobenzofuryl, pyrazolyl,indolyl, purinyl, carbazolyl, benzimidazolyl, and isoxazolyl.

“Heterocyclic ring,” as used herein, refers to a stable 5- to 7-memberedmonocyclic or bicyclic or 7- to 10-membered bicyclic heterocyclic ringthat is saturated, partially unsaturated or unsaturated (aromatic), andwhich contains carbon atoms and from 1 to 4 heteroatoms independentlyselected from the group consisting of N, O and S and including anybicyclic group in which any of the above defined heterocyclic rings isfused to a benzene ring. The nitrogen and sulfur heteroatoms mayoptionally be oxidized. The heterocyclic ring may be attached to itspendant group at any heteroatom or carbon atom that results in a stablestructure. The heterocyclic rings described herein may be substituted oncarbon or on a nitrogen atom if the resulting compound is stable. Ifspecifically noted, a nitrogen atom in the heterocycle may optionally bequaternized. It is preferred that when the total number of S and O atomsin the heterocycle exceeds one, then these heteroatoms are not adjacentto one another. It is preferred that the total number of S and O atomsin the heterocycle is not more than one. Examples of heterocyclesinclude, but are not limited to, 1H-indazole, 2-pyrrolidonyl,2H,6H-1,5,2-dithiazinyl, 2H-pyrrolyl, 3H-indolyl, 4-piperidonyl,4aH-carbazole, 4H-quinolizinyl, 6H-1,2,5-thiadiazinyl, acridinyl,azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl,benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl,benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalonyl,carbazolyl, 4H-carbazolyl, α-, β-, or γ-carbolinyl, chromanyl,chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl,dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl,imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl,indolizinyl, indolyl, isobenzofuranyl, isochromanyl, isoindazolyl,isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl,morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl,1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl,1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinylpyrimidinyl,phenanthridinyl, phenanthrolinyl, phenoxazinyl, phenazinyl,phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl,piperidinyl, pteridinyl, piperidonyl, 4-piperidonyl, pteridinyl,purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl,pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl,pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl,quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, carbolinyl,tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl,6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl,thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl,triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl,1,3,4-triazolyl, xanthenyl. Preferred heterocycles include, but are notlimited to, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl,imidazolyl, indolyl, benzimidazolyl, 1H-indazolyl, oxazolidinyl,benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl, or isatinyl.Also included are fused ring and spiro compounds containing, forexample, the above heterocycles.

“Alkoxy,” as used herein, refers to the group R—O— where R is an alkylgroup as defined herein.

“Aryloxy,” as used herein, refers to the group R—O— where R is an arylgroup, as defined herein.

“Heteroaryloxy,” as used herein, refers to the group R—O— where R is aheteroaryl group, as defined herein.

“Alkanoyloxy,” as used herein, refers to the group R—C(═O)—O— where R isan alkyl group of 1 to 5 carbon atoms.

“Alkylsulfoxide,” as used herein, refers to as used herein, refers to—S(═O)—R, where R is alkyl, as defined above.

“Alkylsulfone,” as used herein, refers to —S(═O)₂—R, where R is alkyl,as defined above.

“Alkylsulfonamide,” as used herein, refers to —NR—S(═O)₂—R, where each Ris independently, alkyl, as defined above or the NR part may also be NH.

“Phenylsulfonamide,” as used herein, refers to —NR—S(═O)₂-phenyl, whereR is H or alkyl, as defined above.

“Heteroarylmethyloxy,” as used herein, refers to —OCH₂—R, where R isheteroaryl, as defined above.

“Alkylamido,” as used herein, refers to —NR—C(═O)—R, where each R isindependently, alkyl, as defined above, or the NR part may also be NH.

“Phenylamido,” as used herein, refers to —NR—C(═O)-phenyl, where R is Hor alkyl, as defined above.

“Halo,” as used herein, refers to chloro, bromo, fluoro, and iodo.

In one embodiment, the invention is directed to compounds of formula I:

or a pharmaceutically acceptable salt thereof;

wherein:

the dotted line represents an optional double bond between U and V or Vand W;

U is, independently, O, S, SO, SO₂, C═O, N, NR₃, or C(R₈)₂;

W is CH, CH₂, or C═O;

provided that when W is CH₂, U is not C(R₈)₂;

V is C(R₈), C(R₈)₂, O, or N(R₈);

R₁ is, independently at each occurrence, alkyl, alkoxy, halo, CF₃, OCF₃,arylalkyloxy substituted with 0-3 R₉, aryloxy substituted with 0-3 R₉,aryl substituted with 0-3 R₉, heteroaryl substituted with 0-3 R₉,hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, alkynyl, alkylsulfoxide,phenylsulfoxide substituted with 0-3 R₉, alkylsulfone, phenylsulfonesubstituted with 0-3 R₉, alkylsulfonamide, phenylsulfonamide substitutedwith 0-3 R₉, heteroaryloxy substituted with 0-3 R₉, heteroarylmethyloxysubstituted with 0-3 R₉, alkylamido, or phenylamido substituted with 0-3R₉; or two adjacent R₁ also represent methylenedioxy;

R₂ is aryl substituted with 0-3 R₁ or heteroaryl substituted with 0-3R₁;

R₃ is H, C₁-C₄ alkyl substituted with 0-3 R₁, C₃-C₆ cycloalkyl, orphenyl substituted with 0-3 R₁;

R₄ is, independently at each occurrence, H, C₁-C₄ alkyl, arylalkyl,heteroarylmethyl, cycloheptylmethyl, cyclohexylmethyl,cyclopentylmethyl, or cyclobutylmethyl, or

both R₄ groups, together with the nitrogen through which they areattached, form a heterocyclic ring of 4 to 6 ring atoms, where onecarbon may be optionally replaced with N, O, S, or SO₂, and where anycarbon ring atom or additional N atom may be optionally substituted withC₁-C₄ alkyl, F, or CF₃;

R₅ is H or C₁-C₄ alkyl;

R₆ is H or C₁-C₄ alkyl;

R₇ is, independently at each occurrence, H, or C₁-C₄ alkyl, or

R₇ and R₄ together with the nitrogen to which R₄ is attached form anitrogen-containing ring containing 3-6 carbon atoms;

R₈ is, independently at each occurrence, H, C₁-C₄ alkyl, C₃-C₆heteroalkyl, or aryl substituted with 0-3 R₁;

R₉ is, independently at each occurrence, alkyl, alkoxy, halo, CF₃, OCF₃,hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, alkynyl, alkylsulfoxide,alkylsulfone, alkylsulfonamide, or alkylamido; or two adjacent R₉ alsorepresent methylenedioxy;

n is an integer from 0 to 4;

x is an integer from 1 to 2; and

wherein 1-3 carbon atoms in ring A may optionally be replaced with N.

The dotted line in the ring fused to ring A represents either anoptional double bond between U and V or between V and W. The dotted linebetween the two R₄ groups represents an optional heterocyclic ring of 4to 6 ring atoms that may be formed between the two R₄ groups, togetherwith the nitrogen through which they are attached.

In certain preferred embodiments of compounds of formula I, U is O. Incertain other preferred embodiments, U is S. In certain other preferredembodiments, U is SO. In certain other preferred embodiments, U is SO₂.In certain other preferred embodiments, U is C═O. In certain otherpreferred embodiments, U is NH. In certain other preferred embodiments,U is NR₃. In certain other preferred embodiments, U is CH₂.

In certain preferred embodiments of compounds of formula I, W is CH. Incertain other preferred embodiments, W is CH₂. In certain otherpreferred embodiments, W is C═O.

In certain preferred embodiments of compounds of formula I, V is C(R₈),especially CH. In certain other preferred embodiments, V is C(R₈)₂,especially CH₂. In certain other preferred embodiments, V is O. Incertain other preferred embodiments, V is N(R₈), especially NH.

In certain preferred embodiments of compounds of formula I, R₁ is,independently at each occurrence, alkyl, preferably C₁-C₄ alkyl, morepreferably methyl. In certain other preferred embodiments, R₁ is,independently at each occurrence, alkoxy. In certain other preferredembodiments of compounds, R₁ is, independently at each occurrence, halo,preferably F or Cl. In certain other preferred embodiments, R₁ is,independently at each occurrence, CF₃. In certain other preferredembodiments, R₁ is, independently at each occurrence, OCF₃. In certainother preferred embodiments, R₁ is, independently at each occurrence,benzyloxy substituted with 0-3 R₁. In certain other preferredembodiments, R₁ is, independently at each occurrence, aryloxysubstituted with 0-3 R₁. In certain other preferred embodiments, R₁ is,independently at each occurrence, aryl substituted with 0-3 R₁. Incertain other preferred embodiments, R₁ is, independently at eachoccurrence, heteroaryl substituted with 0-3 R₁. In certain otherpreferred embodiments, R₁ is, independently at each occurrence, hydroxy.In certain other preferred embodiments, R₁ is, independently at eachoccurrence, alkanoyloxy. In certain other preferred embodiments, R₁ is,independently at each occurrence, methylenedioxy. In certain otherpreferred embodiments, R₁ is, independently at each occurrence, nitro.In certain other preferred embodiments, R₁ is, independently at eachoccurrence, nitrile. In certain other preferred embodiments, R₁ is,independently at each occurrence, alkenyl. In certain other preferredembodiments, R₁ is, independently at each occurrence, alkynyl. Incertain other preferred embodiments, R₁ is, independently at eachoccurrence, alkylsulfoxide. In certain other preferred embodiments, R₁is, independently at each occurrence, phenylsulfoxide substituted with0-3 R₁. In certain other preferred embodiments, R₁ is, independently ateach occurrence, alkylsulfone. In certain other preferred embodiments,R₁ is, independently at each occurrence, phenylsulfone substituted with0-3 R₁. In certain other preferred embodiments, R₁ is, independently ateach occurrence, alkylsulfonamide. In certain other preferredembodiments, R₁ is, independently at each occurrence, phenylsulfonamidesubstituted with 0-3 R₁. In certain other preferred embodiments, R₁ is,independently at each occurrence, heteroaryloxy substituted with 0-3 R₁.In certain other preferred embodiments, R₁ is, independently at eachoccurrence, heteroarylmethyloxy substituted with 0-3 R₁. In certainother preferred embodiments, R₁ is, independently at each occurrence,alkylamido. In certain other preferred embodiments, R₁ is, independentlyat each occurrence, phenylamido substituted with 0-3 R₁.

In certain preferred embodiments of compounds of formula I, R₂ is arylsubstituted with 0-3 R₁, preferably substituted with no R₁. In certainpreferred embodiments, R₂ is naphthyl substituted with 0-3 R₁,preferably substituted with no R₁. In certain preferred embodiments, R₂is heteroaryl substituted with 0-3 R₁, preferably substituted with noR₁.

In certain preferred embodiments of compounds of formula I, R₃ is H. Incertain other preferred embodiments, R₃ is C₁-C₄ alkyl, preferably C₁alkyl. In certain other preferred embodiments, R₃ is C₃-C₆ alkyl,preferably C₅-C₆ alkyl. In certain other preferred embodiments, R₃ isphenyl substituted with 0-3 R₁, especially phenyl.

In certain preferred embodiments of compounds of formula I, R₄ is,independently at each occurrence, H. In certain preferred embodiments,R₄ is, independently at each occurrence, C₁-C₄ alkyl, preferably C₁-C₃alkyl, more preferably methyl, ethyl, or isopropyl. In certain preferredembodiments of compounds of formula I, R₄ is, independently at eachoccurrence, benzyl. In certain preferred embodiments, R₄ is,independently at each occurrence, heteroarylmethyl. In certain preferredembodiments, R₄ is, independently at each occurrence, cycloheptylmethyl, cyclohexyl methyl, cyclopentyl methyl, or cyclobutyl methyl.

In certain preferred embodiments of compounds of formula I, both R₄groups, together with the nitrogen through which they are attached, forma heterocyclic ring of 4 to 6 ring atoms, where one carbon may beoptionally replaced with N, O, S, or SO₂, and where any carbon ring atommay be optionally substituted with C₁-C₄ alkyl, F, or CF₃. In certainmore preferred embodiments, both R₄ groups, together with the nitrogenthrough which they are attached, form a pyridine, piperidine,piperazine, or morpholine ring.

In certain preferred embodiments of compounds of formula I, R₅ is,independently at each occurrence, H. In certain preferred embodiments,R₅ is, independently at each occurrence, C₁-C₄ alkyl, preferably C₁-C₃alkyl, more preferably methyl, ethyl, or isopropyl.

In certain preferred embodiments of compounds of formula I, R₆ is,independently at each occurrence, H. In certain preferred embodiments,R₆ is, independently at each occurrence, C₁-C₄ alkyl, preferably C₁-C₃alkyl, more preferably methyl, ethyl, or isopropyl.

In certain preferred embodiments of compounds of formula I, R₇ is,independently at each occurrence, H. In certain preferred embodiments,R₇ is, independently at each occurrence, C₁-C₄ alkyl, preferably C₁-C₃alkyl, more preferably methyl, ethyl, or isopropyl. In certain preferredembodiments of compounds of formula I, R₇ and R₄ together with thenitrogen to which R₄ is attached form a nitrogen-containing ringcontaining 3-6 carbon atoms, especially, pyrrolidinyl, pyrrolyl,piperidinyl, pyridinyl, azepanyl, and azepinyl.

In certain preferred embodiments of compounds of formula I, R₈ is,independently at each occurrence, H. In certain preferred embodiments,R₈ is, independently at each occurrence, C₁-C₄ alkyl, preferably C₁-C₃alkyl, more preferably methyl, ethyl, or isopropyl. In certain preferredembodiments of compounds of formula I, R₈ is, independently at eachoccurrence, C₃-C₆ heteroalkyl, preferably methoxymethyl, ethoxyethyl,methoxyethyl, methylsulfanylmethyl, ethylsulfanylethyl,methylsulfanylethyl, methylaminoethyl, ethylaminoethyl, andmethylaminoethyl. In certain preferred embodiments of compounds offormula I, R₈ is, independently at each occurrence, aryl substitutedwith 0-3 R₁, especially phenyl, tolyl, and xylyl.

In certain preferred embodiments of compounds of formula I, R₉ is,independently at each occurrence, alkyl, preferably C₁-C₆ alkyl, C₁-C₄alkyl, preferably C₁-C₃ alkyl, more preferably methyl, ethyl, orisopropyl. In certain preferred embodiments of compounds of formula I,R₉ is, independently at each occurrence, alkoxy. In certain preferredembodiments of compounds of formula I, R₉ is, independently at eachoccurrence, halo. In certain preferred embodiments of compounds offormula I, R₉ is, independently at each occurrence, CF₃. In certainpreferred embodiments of compounds of formula I, R₉ is, independently ateach occurrence, OCF₃. In certain preferred embodiments of compounds offormula I, R₉ is, independently at each occurrence, hydroxy. In certainpreferred embodiments of compounds of formula I, R₉ is, independently ateach occurrence, alkanoyloxy. In certain preferred embodiments ofcompounds of formula I, R₉ is, independently at each occurrence,methylenedioxy. In certain preferred embodiments of compounds of formulaI, R₉ is, independently at each occurrence, nitro. In certain preferredembodiments of compounds of formula I, R₉ is, independently at eachoccurrence, nitrile. In certain preferred embodiments of compounds offormula I, R₉ is, independently at each occurrence, alkenyl. In certainpreferred embodiments of compounds of formula I, R₉ is, independently ateach occurrence, alkynyl. In certain preferred embodiments of compoundsof formula I, R₉ is, independently at each occurrence, alkylsulfoxide.In certain preferred embodiments of compounds of formula I, R₉ is,independently at each occurrence, alkylsulfone. In certain preferredembodiments of compounds of formula I, R₉ is, independently at eachoccurrence, alkylsulfonamido. In certain preferred embodiments ofcompounds of formula I, R₉ is, independently at each occurrence,alkylamido.

In certain preferred embodiments of compounds of formula I, n is aninteger from 0 to 3. More preferably, n is 0 to 2. Even more preferably,n is 0 to 1. Yet more preferably, n is 0.

In certain preferred embodiments of compounds of formula I, x is aninteger from 1 to 2. More preferably, x is 1.

In certain preferred embodiments of compounds of formula I, 1-2 carbonatoms in ring A may optionally be replaced with N. In certain preferredembodiments, one carbon atom in ring A may optionally be replaced withN. In certain preferred embodiments, no carbon atoms in ring A arereplaced with N.

Preferred compounds of formula I include:

-   1-(2,3-dihydro-4H-1,4-benzoxazin-4-yl)-3-(methylamino)-1-phenylpropan-2-ol;-   3-(methylamino)-1-(4-methyl-3,4-dihydroquinoxalin-1(2H)-yl)-1-phenylpropan-2-ol;-   3-(methylamino)-1-phenyl-1-[4-(2,2,2-trifluoroethyl)-3,4-dihydroquinoxalin-1(2H)-yl]propan-2-ol;-   1-(6-chloro-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-1-(3,5-difluorophenyl)-3-(methylamino)propan-2-ol;-   1-(3-fluorophenyl)-3-(methylamino)-1-(2-methyl-2,3-dihydro-4H-1,4-benzoxazin-4-yl)propan-2-ol;-   1-(6-chloro-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-3-(methylamino)-1-phenylpropan-2-ol;-   3-(methylamino)-1-(6-methyl-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-1-phenylpropan-2-ol;-   1-(6-chloro-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-3-(methylamino)-1-phenylpropan-2-ol;-   1-(6-chloro-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-3-(methylamino)-1-phenylpropan-2-ol;-   1-(6-chloro-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-1-(3-fluorophenyl)-3-(methylamino)propan-2-ol;-   1-(2,2-dimethyl-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-1-(3-fluorophenyl)-3-(methylamino)propan-2-ol;-   1-(2,2-dimethyl-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-3-(methylamino)-1-phenylpropan-2-ol;-   1-(2,3-dihydro-4H-1,4-benzothiazin-4-yl)-1-(3-fluorophenyl)-3-(methylamino)propan-2-ol;-   1-(3-fluorophenyl)-3-(methylamino)-1-(2-phenyl-2,3-dihydro-4H-1,4-benzoxazin-4-yl)propan-2-ol;-   1-(3-fluorophenyl)-3-(methylamino)-1-[2-phenyl-2,3-dihydro-4H-1,4-benzoxazin-4-yl]propan-2-ol;-   1-(3-fluorophenyl)-3-(methylamino)-1-[2-phenyl-2,3-dihydro-4H-1,4-benzoxazin-4-yl]propan-2-ol;    and

pharmaceutically acceptable salts thereof, particularly dihydrochloridesalts thereof.

Particularly preferred compounds of formula I include:

-   (1RS,2SR)-1-(2,3-dihydro-4H-1,4-benzoxazin-4-yl)-3-(methylamino)-1-phenylpropan-2-ol;-   (1S*,2R*)-3-(methylamino)-1-(4-methyl-3,4-dihydroquinoxalin-1(2H)-yl)-1-phenylpropan-2-ol;-   (1S*,2R*)-3-(methylamino)-1-phenyl-1-[4-(2,2,2-trifluoroethyl)-3,4-dihydroquinoxalin-1(2H)-yl]propan-2-ol;-   (1S,2R)-1-(6-chloro-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-1-(3,5-difluorophenyl)-3-(methylamino)propan-2-ol;-   (1S,2R)-1-(3-fluorophenyl)-3-(methylamino)-1-(2-methyl-2,3-dihydro-4H-1,4-benzoxazin-4-yl)propan-2-ol;-   (1S*,2R*)-1-(6-chloro-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-3-(methylamino)-1-phenylpropan-2-ol;-   (1S*,2R*)-3-(methylamino)-1-(6-methyl-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-1-phenylpropan-2-ol;-   (1S,2R)-1-(6-chloro-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-3-(methylamino)-1-phenylpropan-2-ol;-   (1R,2S)-1-(6-chloro-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-3-(methylamino)-1-phenylpropan-2-ol;-   (1S,2R)-1-(6-chloro-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-1-(3-fluorophenyl)-3-(methylamino)propan-2-ol;-   (1S,2R)-1-(2,2-dimethyl-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-1-(3-fluorophenyl)-3-(methylamino)propan-2-ol;-   (1S,2R)-1-(2,2-dimethyl-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-3-(methylamino)-1-phenylpropan-2-ol;-   (1S,2R)-1-(2,3-dihydro-4H-1,4-benzothiazin-4-yl)-1-(3-fluorophenyl)-3-(methylamino)propan-2-ol;-   (1S,2R)-1-(3-fluorophenyl)-3-(methylamino)-1-(2-phenyl-2,3-dihydro-4H-1,4-benzoxazin-4-yl)propan-2-ol;-   (1S,2R)-1-(3-fluorophenyl)-3-(methylamino)-1-[(2R)-2-phenyl-2,3-dihydro-4H-1,4-benzoxazin-4-yl]propan-2-ol;-   (1S,2R)-1-(3-fluorophenyl)-3-(methylamino)-1-[(2S)-2-phenyl-2,3-dihydro-4H-1,4-benzoxazin-4-yl]propan-2-ol;    and

pharmaceutically acceptable salts thereof, particularly dihydrochloridesalts thereof.

Some of the compounds of the present invention may contain chiralcenters and such compounds may exist in the form of stereoisomers (i.e.enantiomers). The present invention includes all such stereoisomers andany mixtures thereof including racemic mixtures. Racemic mixtures of thestereoisomers as well as the substantially pure stereoisomers are withinthe scope of the invention. The term “substantially pure,” as usedherein, refers to at least about 90 mole %, more preferably at leastabout 95 mole %, and most preferably at least about 98 mole % of thedesired stereoisomer is present relative to other possiblestereoisomers. Preferred enantiomers may be isolated from racemicmixtures by any method known to those skilled in the art, including highperformance liquid chromatography (HPLC) and the formation andcrystallization of chiral salts or prepared by methods described herein.See, for example, Jacques, et al., Enantiomers, Racemates andResolutions (Wiley Interscience, New York, 1981); Wilen, S. H., et al.,Tetrahedron, 33:2725 (1977); Eliel, E. L. Stereochemistry of CarbonCompounds, (McGraw-Hill, NY, 1962); Wilen, S. H. Tables of ResolvingAgents and Optical Resolutions, p. 268 (E. L. Eliel, Ed., University ofNotre Dame Press, Notre Dame, Ind. 1972).

The present invention includes prodrugs of the compounds of formula I.“Prodrug,” as used herein, means a compound which is convertible in vivoby metabolic means (e.g. by hydrolysis) to a compound of formula I.Various forms of prodrugs are known in the art, for example, asdiscussed in Bundgaard, (ed.), Design of Prodrugs, Elsevier (1985);Widder, et al. (ed.), Methods in Enzymology, vol. 4, Academic Press(1985); Krogsgaard-Larsen, et al., (ed). “Design and Application ofProdrugs,” Textbook of Drug Design and Development, Chapter 5, 113-191(1991), Bundgaard, et al., Journal of Drug Deliver Reviews, 1992,8:1-38, Bundgaard, J. of Pharmaceutical Sciences, 1988, 77:285 et seq.;and Higuchi and Stella (eds.) Prodrugs as Novel Drug Delivery Systems,American Chemical Society (1975).

Further, the compounds of formula I may exist in unsolvated as well asin solvated forms with pharmaceutically acceptable solvents such aswater, ethanol, and the like. In general, the solvated forms areconsidered equivalent to the unsolvated forms for the purpose of thepresent invention.

The compounds of the present invention may be prepared in a number ofways well known to those skilled in the art. The compounds can besynthesized, for example, by the methods described below, or variationsthereon as appreciated by the skilled artisan. All processes disclosedin association with the present invention are contemplated to bepracticed on any scale, including milligram, gram, multigram, kilogram,multikilogram or commercial industrial scale.

As will be readily understood, functional groups present may containprotecting groups during the course of synthesis. Protecting groups areknown per se as chemical functional groups that can be selectivelyappended to and removed from functionalities, such as hydroxyl groupsand carboxyl groups. These groups are present in a chemical compound torender such functionality inert to chemical reaction conditions to whichthe compound is exposed. Any of a variety of protecting groups may beemployed with the present invention. Protecting groups that may beemployed in accordance with the present invention may be described inGreene, T. W. and Wuts, P. G. M., Protective Groups in Organic Synthesis2d. Ed., Wiley & Sons, 1991.

Compounds of the present invention are suitably prepared in accordancewith the following general description and specific examples. Variablesused are as defined for formula I, unless otherwise noted. The reagentsused in the preparation of the compounds of this invention can be eithercommercially obtained or can be prepared by standard proceduresdescribed in the literature.

The compounds of this invention contain chiral centers, providingvarious stereoisomeric forms such as enantiomeric mixtures as well asoptical isomers. The individual optical isomers can be prepared directlythrough asymmetric and/or stereospecific synthesis or by conventionalchiral separation of optical isomers from the enantiomeric mixture.

Compounds of the present invention are suitably prepared in accordancewith the following general description and specific examples. Variablesused are as defined for formula I, unless otherwise noted. The reagentsused in the preparation of the compounds of this invention can be eithercommercially obtained or can be prepared by standard proceduresdescribed in the literature.

The compounds of this invention contain chiral centers, providingvarious stereoisomeric forms such as enantiomeric mixtures as well asoptical isomers. The individual optical isomers can be prepared directlythrough asymmetric and/or stereospecific synthesis or by conventionalchiral separation of optical isomers from the enantiomeric mixture.

In accordance with this invention, compounds of formula I are producedby the following reaction schemes (Schemes I to VII). Depending on thedesired diastereomer, the compounds are prepared via different syntheticroutes (diastereomer A—Schemes I and III, and diastereomer B—Scheme IV).If it is desired to synthesize compounds of formula I-a, they can beprepared from compounds of formula 18 and 19 in three steps beginningwith a regio- and stereo-selective ring opening of an epoxide of formula19 with an appropriately substituted compound of formula 18 to producecompounds of formula 20 (Scheme 1). Any conventional method for theregio- and stereo-selective opening of an epoxide can be utilized forthis conversion. In accordance with the preferred embodiment of thisinvention, compounds of formula 18 are heated with compounds of formula19 at temperatures from about 120° C. to about 150° C. in the absence ofsolvent to afford compounds of formula 20. Compounds of formula 21 canbe formed from compounds of formula 20 via direct amidation with anappropriate amine. Any conventional method for direct conversion of anester to an amide can be utilized for this conversion. In accordancewith the preferred embodiment of this invention, compounds of formula 20are heated in a sealed tube at temperatures between about 50° C. toabout 100° C. with an excess of alcoholic amine to form compounds offormula 21 which can be reduced to form compounds of formula I-a. Anyconventional method for reduction of an amide can be utilized for thisconversion. In accordance with the preferred embodiment of thisinvention, compounds of formula are heated with borane-tetrahydrofurancomplex at temperatures between about 50° C. and about 90° C. to affordcompounds of formula I-a that can be converted to a pharmaceuticallyacceptable salt using any conventional method.

-   Where: A, R₁, n, R₂, R₄, R₈, R₉, U, V and W are as previously    described. T=C₁-C₄ lower alkyl

If it is desired to produce compounds of formula I-aa, they can beprepared via alkylation of compounds of formula 20 (Scheme III). Anyconventional method for the alkylation of secondary alcohols can beemployed for this conversion. In accordance with the preferredembodiment of this invention, compounds of formula are treated with analkyl halide using sodium hydride as base to afford compounds of formula21. Compounds of formula 21 can be converted in two steps to compoundsof formula I-aa in an identical manner as previously described for theconversion of compounds of formula 20 to compounds of formula I-a(Scheme I). Compounds of formula I-a can be converted into apharmaceutically acceptable salt using any conventional method.

-   Where: A, R₁, n, R₂, R₄, R₈, R₉, U, V and W are as previously    described R₃=C₁-C₃ lower alkyl; T=C₁-C₄ lower alkyl

Alternatively, compounds of formula I-a and I-aa can be formed fromcompounds of formula 23 (Scheme III). Compounds of formula I-a can beformed from compounds of formula 23 by selectively converting theprimary alcohol into a leaving group and displacing it with a desiredamine. Any conventional method for the selective conversion of a primaryalcohol into a leaving group and displacing it with an amine can beutilized for this conversion. In accordance with the preferredembodiment of this invention, the diol of formula 23 is treated withpara-toluenesulfonyl chloride in pyridine to form the tosylate offormula 24, which is converted to the compound of formula I-a viatreatment with an excess of an alcoholic amine solution, either at roomtemperature or heated to about 40° C. to about 80° C. in a sealed tube.Compounds of formula I-a can be converted to a pharmaceuticallyacceptable salt using any conventional method.

If it is desired to form compounds of formula I-aa, they can be preparedfrom compounds of formula 24 via alkylation followed by amination. Anyconventional method of alkylating a hydroxyl group in the presence of atosyl group can be employed for this conversion. In accordance with thepreferred embodiment of this invention, compounds of formula 24 aretreated with an alkyl trifluoromethanesulfonate, e.g. methyltrifluoromethanesulfonate, in the presence of a hindered base, e.g.2,6-di-tert-butyl-4-methylpyridine. The reaction can be performed eitherat room temperature or heated to about 40° C. to about 80° C. Compoundsof formula 25 can be converted to compounds of formula I-aa aspreviously described for the synthesis of compounds of formula I-a.Compounds of formula I-aa can be converted to a pharmaceuticallyacceptable salt using any conventional method.

-   Where: A, R₁, n, R₂, R₄, R₈, R₉, R₁₀, U, V and W are as previously    described R₃=C₁-C₃ lower alkyl; OTs=para-toluenesulfonylate or any    conventional leaving group

If it is desired to form compounds of formula I-b, they can be formedfrom compounds of formula 23 (Scheme IV). Compounds of formula 23 can beconverted in four steps to compounds of formula I-b. This route involvesthe selective protection of the primary alcohol followed by conversionof the secondary alcohol to a leaving group. Any conventional method forthe selective protection of a primary alcohol, and any conventionalmethod for converting of a secondary alcohol into a leaving group can beutilized for this conversion. In accordance with the preferredembodiment of this invention, compounds of formula 23 are treated withpara-nitrobenzoyl chloride in pyridine at low temperature (preferablybelow about 0° C.) to form compounds of formula 26. Compounds of formula26 can be converted to a secondary mesylate of formula 27 via reactionwith methanesulfonyl chloride in dichloromethane using triethylamine asbase. The reaction is preferably carried out at temperatures betweenabout −15° C. and about 10° C. Deprotection of the primary alcohol incompounds of formula 27 allows for the formation of a primary epoxidethrough an S_(N)2 reaction resulting in an inversion of thestereocenter. Any conventional method for deprotection of a primaryalcohol, and any conventional method for epoxide formation onto an alphaleaving group can be employed for this conversion. In accordance withthe preferred embodiment of this invention, compounds of formula 27 aretreated with an aqueous solution of a suitable base in organic solvent,preferably, aqueous sodium hydroxide in dioxane. The resulting epoxideof formula 28 can be ring-opened regioselectively with an amine toproduce the desired aminoalcohol of formula I-b. Any conventional methodfor the regioselective ring opening of a primary epoxide can be employedfor this conversion. In accordance with the preferred embodiment of thisinvention, compounds of formula 28 are treated with an excess of analcoholic amine solution in a sealed flask, either at room temperatureor heated to about 40° C. to about 90° C. Compounds of formula I-b canbe converted to a pharmaceutically acceptable salt using anyconventional method.

-   Where A, R₁, n, R₂, R₄, R₈, R₁₀, U, V and W are as previously    described R₉ is H    -   PNB=para-nitrobenzoyl or any conventional protecting group;        OMs=methanesulfonate or any conventional leaving group; T=C₁-C₄        lower alkyl

If it is desired to form compounds of formula I-bb, they can be formedfrom compounds of formula I-b in three steps (Scheme V) in an identicalmanner as previously described for the conversion of compounds offormula I-b to compounds of formula I-bb (Scheme III). Compounds offormula I-bb can be converted to a pharmaceutically acceptable saltusing any conventional method.

-   Where: A, R₁, n, R₂, R₄, R₈, R₉, R₁₀, U, V and W are as previously    described R₃=C₁-C₃ lower alkyl, P=protecting group, preferably    tert-butoxycarbonyl

Compounds of formula 23 are formed via regio- and stereo-selective ringopening of an appropriately substituted epoxide of formula 17 (formedvia an epoxidation of an appropriately substituted allylic alcohol) withan appropriately substituted compound of formula 18 (Scheme VI). Anyconventional method for regio- and stereo-selective ring opening of anepoxide can be employed for this conversion. In accordance with thepreferred embodiment of this invention, compounds of formula 18 aretreated with a base, e.g. sodium hydride, sodium tert-butoxide,potassium hydroxide, potassium tert-butoxide or potassium hydroxide,then treated with the epoxide of formula 17. The epoxide of formula 17can be pre-treated with a Lewis acid, e.g. titanium iso-propoxide,boron-trifluoride, etc. to ensure regio-selective ring-opening. Thereaction occurs at room temperature over a duration of about 2 to about72 hours. Alternatively, compounds of formula 18 that are suitablynucleophilic can be heated with the epoxide of formula 17 attemperatures from about 50° C. to about 170° C. to form compounds offormula 23.

Epoxidation of trans-allylic alcohols can be performed eitherracemically or asymmetrically using methods described in the literature.In accordance with the preferred embodiment of this invention, racemicepoxidation is conducted with either peracetic acid ormeta-chloroperbenzoic acid. If it is desired to produce a singleenantiomer of compounds of formula I, asymmetric epoxidation of anallylic alcohol can be performed with tert-butylhydroperoxide or cumenehydroperoxide in the presence of the appropriate tartrate ester,titanium (IV) isopropoxide, and molecular sieves. This method is wellestablished in the literature (e.g. K. B. Sharpless, et. al., J. Org.Chem. 1986, 51, 3710). Compounds of formula 18 and the starting allylicalcohols are either available from commercial sources or are accessiblethrough methods well established in the literature.

Where: A, R₁, n, R₂, R₈, R₉, R₁₀, U, V and W are as previously described

Compounds of formula 19 can be formed either racemically orasymmetrically using methods described in the literature starting witheither trans-allylic esters or trans-allylic alcohols (Scheme VII). Inaccordance with the preferred embodiment of this invention, racemicepoxidation of the trans-allylic ester is conducted usingdi-(trifluoromethyl)dioxirane formed in-situ from trifluoroacetone andoxone (Yang, D.; Wong, M.-K.; Yip J. Org. Chem. 1995, 60, 3887-3889). Ifit is desired to produce a single enantiomer of compounds of formula I,asymmetric epoxidation of an allylic ester can be performed with oxoneand a chiral ketone as reported in the literature (W-Y. Wu, X. She, Y.Shi, J. Am. Chem. Soc. 2002, 124, 8792). Alternatively, compounds offormula 19 can be formed via the oxidation and esterification ofcompounds of formula 17 (described in Scheme VI). Any conventionalmethod for the oxidation of an epoxy alcohol and any conventional methodfor the esterification of an epoxy acid can be utilized for thisconversion. In accordance with the preferred embodiment of thisinvention, epoxy alcohol 17 is oxidized with sodium periodate andcatalytic ruthenium trichloride in carbon tetrachloride, buffered withsodium bicarbonate. The resulting acid can be esterified withdiazomethane or with catalytic sulfuric acid in ethanol to formcompounds of formula 19.

Where: R₂, R₈ and R₉ are as previously describedAnd where: T=C₁-C₄ lower alkyl

In other embodiments, the invention is directed to pharmaceuticalcompositions, comprising:

-   a. at least compound of formula I, or pharmaceutically acceptable    salt thereof; and-   b. at least one pharmaceutically acceptable carrier.    Generally, the compound of formula I, or a pharmaceutically    acceptable salt thereof, will be present at a level of from about    0.1%, by weight, to about 90% by weight, based on the total weight    of the pharmaceutical composition, based on the total weight of the    pharmaceutical composition. Preferably, the compound of formula I,    or a pharmaceutically acceptable salt thereof, will be present at a    level of at least about 1%, by weight, based on the total weight of    the pharmaceutical composition. More preferably, the compound of    formula I, or a pharmaceutically acceptable salt thereof, will be    present at a level of at least about 5%, by weight, based on the    total weight of the pharmaceutical composition. Even more    preferably, the norepinephrine reuptake inhibitor or a    pharmaceutically acceptable salt thereof will be present at a level    of at least about 10%, by weight, based on the total weight of the    pharmaceutical composition. Yet even more preferably, the compound    of formula I, or a pharmaceutically acceptable salt thereof, will be    present at a level of at least about 25%, by weight, based on the    total weight of the pharmaceutical composition.

Such compositions are prepared in accordance with acceptablepharmaceutical procedures, such as described in Remington'sPharmaceutical Sciences, 17th edition, ed. Alfonoso R. Gennaro, MackPublishing Company, Easton, Pa. (1985). Pharmaceutically acceptablecarriers are those that are compatible with the other ingredients in theformulation and biologically acceptable.

The compounds of this invention may be administered orally orparenterally, neat or in combination with conventional pharmaceuticalcarriers. Applicable solid carriers can include one or more substancesthat may also act as flavoring agents, lubricants, solubilizers,suspending agents, fillers, glidants, compression aids, binders ortablet-disintegrating agents or an encapsulating material. In powders,the carrier is a finely divided solid that is in admixture with thefinely divided active ingredient. In tablets, the active ingredient ismixed with a carrier having the necessary compression properties insuitable proportions and compacted in the shape and size desired. Thepowders and tablets preferably contain up to 99% of the activeingredient. Suitable solid carriers include, for example, calciumphosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch,gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose,polyvinylpyrrolidine, low melting waxes and ion exchange resins.

Liquid carriers may be used in preparing solutions, suspensions,emulsions, syrups, and elixirs. The active ingredient of this inventioncan be dissolved or suspended in a pharmaceutically acceptable liquidcarrier such as water, an organic solvent, a mixture of both orpharmaceutically acceptable oils or fat. The liquid carrier can containother suitable pharmaceutical additives such as solubilizers,emulsifiers, buffers, preservatives, sweeteners, flavoring agents,suspending agents, thickening agents, colors, viscosity regulators,stabilizers, or osmo-regulators. Suitable examples of liquid carriersfor oral and parenteral administration include water (particularlycontaining additives as above, e.g. cellulose derivatives, preferablysodium carboxymethyl cellulose solution), alcohols (including monohydricalcohols and polyhydric alcohols, e.g. glycols) and their derivatives,and oils (e.g. fractionated coconut oil and arachis oil). For parenteraladministration, the carrier can also be an oily ester such as ethyloleate and isopropyl myristate. Sterile liquid carriers are used insterile liquid form compositions for parenteral administration.

Liquid pharmaceutical compositions, which are sterile solutions orsuspensions, can be administered by, for example, intramuscular,intraperitoneal or subcutaneous injection. Sterile solutions can also beadministered intravenously. Oral administration may be either liquid orsolid composition form.

Preferably the pharmaceutical composition is in unit dosage form, e.g.as tablets, capsules, powders, solutions, suspensions, emulsions,granules, or suppositories. In such form, the composition is sub-dividedin unit dose containing appropriate quantities of the active ingredient;the unit dosage forms can be packaged compositions, for example packetedpowders, vials, ampoules, prefilled syringes or sachets containingliquids. The unit dosage form can be, for example, a capsule or tabletitself, or it can be the appropriate number of any such compositions inpackage form.

In another embodiment of the present invention, the compounds useful inthe present invention may be administered to a mammal with one or moreother pharmaceutical active agents such as those agents being used totreat any other medical condition present in the mammal. Examples ofsuch pharmaceutical active agents include pain relieving agents,anti-angiogenic agents, anti-neoplastic agents, anti-diabetic agents,anti-infective agents, or gastrointestinal agents, or combinationsthereof.

The one or more other pharmaceutical active agents may be administeredin a therapeutically effective amount simultaneously (such asindividually at the same time, or together in a pharmaceuticalcomposition), and/or successively with one or more compounds of thepresent invention.

The term “combination therapy” refers to the administration of two ormore therapeutic agents or compounds to treat a therapeutic condition ordisorder described in the present disclosure, for example hot flush,sweating, thermoregulatory-related condition or disorder, or other. Suchadministration includes use of each type of therapeutic agent in aconcurrent manner. In either case, the treatment regimen will providebeneficial effects of the drug combination in treating the conditions ordisorders described herein.

The route of administration may be any route, which effectivelytransports the active compound of formula I, or a pharmaceuticallyacceptable salt thereof, to the appropriate or desired site of action,such as oral, nasal, pulmonary, transdermal, such as passive oriontophoretic delivery, or parenteral, e.g. rectal, depot, subcutaneous,intravenous, intraurethral, intramuscular, intranasal, ophthalmicsolution or an ointment. Furthermore, the administration of compound offormula I, or pharmaceutically acceptable salt thereof, with otheractive ingredients may be concurrent or simultaneous.

It is believed that the present invention described presents asubstantial breakthrough in the field of treatment, alleviation,inhibition, and/or prevention of conditions ameliorated by monoaminereuptake including, inter alia, vasomotor symptoms (VMS), sexualdysfunction, gastrointestinal and genitourinary disorders, chronicfatigue syndrome, fibromyalgia syndrome, nervous system disorders, andcombinations thereof, particularly those conditions selected from thegroup consisting of major depressive disorder, vasomotor symptoms,stress and urge urinary incontinence, fibromyalgia, pain, diabeticneuropathy, and combinations thereof.

Accordingly, in one embodiment, the present invention is directed tomethods for treating or preventing a condition ameliorated by monoaminereuptake in a subject in need thereof, comprising the step of:

administering to said subject an effective amount of a compound offormula I or pharmaceutically acceptable salt thereof.

The conditions ameliorated by monoamine reuptake include those selectedfrom the group consisting of vasomotor symptoms, sexual dysfunction,gastrointestinal and genitourinary disorders, chronic fatigue syndrome,fibromyalgia syndrome, nervous system disorders, and combinationsthereof, particularly those conditions selected from the groupconsisting of major depressive disorder, vasomotor symptoms, stress andurge urinary incontinence, fibromyalgia, pain, diabetic neuropathy, andcombinations thereof.

“Vasomotor symptoms,” “vasomotor instability symptoms” and “vasomotordisturbances” include, but are not limited to, hot flushes (flashes),insomnia, sleep disturbances, mood disorders, irritability, excessiveperspiration, night sweats, fatigue, and the like, caused by, interalia, thermoregulatory dysfunction.

The term “hot flush” is an art-recognized term that refers to anepisodic disturbance in body temperature typically consisting of asudden skin flushing, usually accompanied by perspiration in a subject.

The term “sexual dysfunction” includes, but is not limited to, conditionrelating to desire and/or arousal.

As used herein, “gastrointestinal and genitourinary disorders” includesirritable bowel syndrome, symptomatic GERD, hypersensitive esophagus,nonulcer dyspepsia, noncardiac chest pain, biliary dyskinesia, sphincterof Oddi dysfunction, incontinence (i.e., urge incontinence, stressincontinence, genuine stress incontinence, and mixed incontinence)(including the involuntary voiding of feces or urine, and dribbling orleakage or feces or urine which may be due to one or more causesincluding but not limited to pathology altering sphincter control, lossof cognitive function, overdistention of the bladder, hyperreflexiaand/or involuntary urethral relaxation, weakness of the musclesassociated with the bladder or neurologic abnormalities), interstitialcystitis (irritable bladder), and chronic pelvic pain (including, butnot limited to vulvodynia, prostatodynia, and proctalgia).

As used herein, “chronic fatigue syndrome” (CFS) is a conditioncharacterized by physiological symptoms selected from weakness, muscleaches and pains, excessive sleep, malaise, fever, sore throat, tenderlymph nodes, impaired memory and/or mental concentration, insomnia,disordered sleep, localized tenderness, diffuse pain and fatigue, andcombinations thereof.

As used herein, “fibromyalgia syndrome” (FMS) includes FMS and othersomatoform disorders, including FMS associated with depression,somatization disorder, conversion disorder, pain disorder,hypochondriasis, body dysmorphic disorder, undifferentiated somatoformdisorder, and somatoform NOS. FMS and other somatoform disorders areaccompanied by physiological symptoms selected from a generalizedheightened perception of sensory stimuli, abnormalities in painperception in the form of allodynia (pain with innocuous stimulation),abnormalities in pain perception in the form of hyperalgesia (increasedsensitivity to painful stimuli), and combinations thereof.

As used herein, “nervous system disorders,” includes addictive disorders(including those due to alcohol, nicotine, and other psychoactivesubstances) and withdrawal syndrome, age-associated learning and mentaldisorders (including Alzheimer's disease), anorexia nervosa, bulimianervosa, attention-deficit disorder with or without hyperactivitydisorder bipolar disorder, pain, cyclothymic disorder, depressiondisorder (including major depressive disorder, refractory depressionadolescent depression and minor depression), dysthymic disorder,generalized anxiety disorder (GAD), obesity (i.e., reducing the weightof obese or overweight patients), obsessive compulsive disorders andrelated spectrum disorders, oppositional defiant disorder, panicdisorder, post-traumatic stress disorder, premenstrual dysphoricdisorder (i.e., premenstrual syndrome and late luteal phase dysphoricdisorder), psychotic disorders (including schizophrenia, schizoaffectiveand schizophreniform disorders), seasonal affective disorder, sleepdisorders (such as narcolepsy and enuresis), social phobia (includingsocial anxiety disorder), selective serotonin reuptake inhibition (SSRI)“poop out” syndrome (i.e., wherein a patient who fails to maintain asatisfactory response to SSRI therapy after an initial period ofsatisfactory response).

As used herein, “pain,” includes both acute pain and chronic pain, whichmay be centralized pain, peripheral pain, or combination thereof. Theterm includes many different types of pains including, but not limitedto, neuropathic pain, visceral pain, musculoskeletal pain, bony pain,cancer pain, inflammatory pain, and combinations thereof, such as lowerback pain, atypical chest pain, headache such as cluster headache,migraine, herpes neuralgia, phantom limb pain, pelvic pain, myofascialface pain, abdominal pain, neck pain, central pain, dental pain, opioidresistant pain, visceral pain, surgical pain, bone injury pain, painduring labor and delivery, pain resulting from burns, post partum pain,angina pain, neuropathic pain such as peripheral neuropathy and diabeticneuropathy, post-operative pain, and pain which is co-morbid withnervous system disorders described herein.

As used herein, the term “acute pain” refers to centralized orperipheral pain that is intense, localized, sharp, or stinging, and/ordull, aching, diffuse, or burning in nature and that occurs for shortperiods of time.

As used herein, the term “chronic pain” refers to centralized orperipheral pain that is intense, localized, sharp, or stinging, and/ordull, aching, diffuse, or burning in nature and that occurs for extendedperiods of time (i.e., persistent and/or regularly reoccurring),including, for the purpose of the present invention, neuropathic painand cancer pain. Chronic pain includes neuropathic pain, hyperalgesia,and/or allodynia.

As used herein, the term “neuropathic pain” refers to chronic paincaused by damage to or pathological changes in the peripheral or centralnervous systems. Examples of pathological changes related to neuropathicpain include prolonged peripheral or central neuronal sensitization,central sensitization related damage to nervous system inhibitory and/orexhibitory functions and abnormal interactions between theparasympathetic and sympathetic nervous systems. A wide range ofclinical conditions may be associated with or form the basis forneuropathic pain including, for example, diabetes, post traumatic painof amputation (nerve damage cause by injury resulting in peripheraland/or central sensitization such as phantom limb pain), lower backpain, cancer, chemical injury, toxins, other major surgeries, peripheralnerve damage due to traumatic injury compression, post-herpeticneuralgia, trigeminal neuralgia, lumbar or cervical radiculopathies,fibromyalgia, glossopharyngeal neuralgia, reflex sympathetic dystrophy,casualgia, thalamic syndrome, nerve root avulsion, reflex sympatheticdystrophy or post thoracotomy pain, nutritional deficiencies, or viralor bacterial infections such as shingles or human immunodeficiency virus(HIV), and combinations thereof. Also included in the definition ofneuropathic pain is a condition secondary to metastatic infiltration,adiposis dolorosa, burns, central pain conditions related to thalamicconditions, and combinations thereof.

As used herein, the term “hyperalgesia” refers to pain where there is anincrease in sensitivity to a typically noxious stimulus.

As used herein, the term “allodynia” refers to an increase insensitivity to a typically non-noxious stimulus.

As used herein, the term “visceral pain” refers to pain associated withor resulting from maladies of the internal organs, such as, for example,ulcerative colitis, irritable bowel syndrome, irritable bladder, Crohn'sdisease, rheumatologic (arthralgias), tumors, gastritis, pancreatitis,infections of the organs, biliary tract disorders, and combinationsthereof.

As used herein, the term “female-specific pain” refers to pain that maybe acute and/or chronic pain associated with female conditions. Suchgroups of pain include those that are encountered solely orpredominately by females, including pain associated with menstruation,ovulation, pregnancy or childbirth, miscarriage, ectopic pregnancy,retrograde menstruation, rupture of a follicular or corpus luteum cyst,irritation of the pelvic viscera, uterine fibroids, adenomyosis,endometriosis, infection and inflammation, pelvic organ ischemia,obstruction, intra-abdominal adhesions, anatomic distortion of thepelvic viscera, ovarian abscess, loss of pelvic support, tumors, pelviccongestion or referred pain from non-gynecological causes, andcombinations thereof.

In one embodiment, the present invention is directed to methods fortreating or preventing vasomotor symptoms in a subject in need thereof,comprising the step of:

administering to said subject an effective amount of at least onecompound of formula I or pharmaceutically acceptable salt thereof.

When estrogen levels are low or estrogen is absent, the normal levelsbetween NE and 5-HT is altered and this altered change inneurotransmitter levels may result in changes in the sensitivity of thethermoregulatory center. The altered chemical levels may be translatedin the thermoregulatory center as heat sensation and as a response, thehypothalamus may activate the descending autonomic pathways and resultin heat dissipation via vasodilation and sweating (hot flush) (FIG. 1).Accordingly, the estrogen deprivation may result in alterednorepinephrine activity.

Norepinephrine synthesized in perikarya of the brainstem is released atthe nerve terminals in the hypothalamus and brainstem. In thehypothalamus, NE regulates the activity of neurons residing in thethermoregulatory center. In the brainstem, NE innervates serotoninergicneurons (5HT), and acting via adrenergic_(α1) and adrenergic_(α2)postsynaptic receptors, it stimulates the activity of the serotoninergicsystem. In response, 5-HT neurons also modulate the activity thethermoregulatory center and feedback to NE neurons. Via this feedbackconnection, 5-HT, acting via 5-HT_(2a) receptors, inhibit the activityof NE neurons. Norepinephrine in the synaptic cleft is also taken up byNE transporter (NET) located in NE neurons. The transporter recycles NEand makes it available for multiple neurotransmission (FIG. 2).

The present invention provides a treatment for vasomotor symptoms bymethods of recovering the reduced activity of norepinephrine.Norepinephrine activity in the hypothalamus or in the brainstem can beelevated by (i) blocking the activity of the NE transporter, (ii)blocking the activity of the presynaptic adrenergic_(α2) receptor withan antagonist, or (iii) blocking the activity of 5-HT on NE neurons witha 5-HT_(2a) antagonist.

In another embodiment, the present invention is directed to methods fortreating or preventing a depression disorder in a subject in needthereof, comprising the step of:

administering to said subject an effective amount of at least onecompound of formula I or pharmaceutically acceptable salt thereof.

In yet other embodiments, the present invention is directed to methodsfor treating or preventing sexual dysfunction in a subject in needthereof, comprising the step of:

administering to said subject an effective amount of at least onecompound of formula I or pharmaceutically acceptable salt thereof.

In another embodiment, the present invention is directed to methods fortreating or preventing gastrointestinal or genitourinary disorder,particularly stress incontinence or urge urinary incontinence, in asubject in need thereof, comprising the step of:

administering to said subject an effective amount of a compound offormula I or pharmaceutically acceptable salt thereof.

In another embodiment, the present invention is directed to methods fortreating or preventing chronic fatigue syndrome in a subject in needthereof, comprising the step of:

administering to said subject an effective amount of a compound offormula I or pharmaceutically acceptable salt thereof.

In another embodiment, the present invention is directed to methods fortreating or preventing fibromyalgia syndrome in a subject in needthereof, comprising the step of:

administering to said subject an effective amount of a compound offormula I or pharmaceutically acceptable salt thereof.

In further embodiments, the present invention is directed to methods fortreating or preventing pain in a subject in need thereof, comprising thestep of:

administering to said subject an effective amount of at least onecompound of formula I or pharmaceutically acceptable salt thereof.

The pain may be, for example, acute pain (short duration) or chronicpain (regularly reoccurring or persistent). The pain may also becentralized or peripheral.

Examples of pain that can be acute or chronic and that can be treated inaccordance with the methods of the present invention includeinflammatory pain, musculoskeletal pain, bony pain, lumbosacral pain,neck or upper back pain, visceral pain, somatic pain, neuropathic pain,cancer pain, pain caused by injury or surgery such as burn pain ordental pain, or headaches such as migraines or tension headaches, orcombinations of these pains. One skilled in the art will recognize thatthese pains may overlap one another. For example, a pain caused byinflammation may also be visceral or musculoskeletal in nature.

In a preferred embodiment of the present invention the compounds usefulin the present invention are administered in mammals to treat chronicpain such as neuropathic pain associated for example with damage to orpathological changes in the peripheral or central nervous systems;cancer pain; visceral pain associated with for example the abdominal,pelvic, and/or perineal regions or pancreatitis; musculoskeletal painassociated with for example the lower or upper back, spine,fibromyalgia, temporomandibular joint, or myofascial pain syndrome; bonypain associated with for example bone or joint degenerating disorderssuch as osteoarthritis, rheumatoid arthritis, or spinal stenosis;headaches such migraine or tension headaches; or pain associated withinfections such as HIV, sickle cell anemia, autoimmune disorders,multiple sclerosis, or inflammation such as osteoarthritis or rheumatoidarthritis.

In a more preferred embodiment, the compounds useful in this inventionare used to treat chronic pain that is neuropathic pain, visceral pain,musculoskeletal pain, bony pain, cancer pain or inflammatory pain orcombinations thereof, in accordance with the methods described herein.Inflammatory pain can be associated with a variety of medical conditionssuch as osteoarthritis, rheumatoid arthritis, surgery, or injury.Neuropathic pain may be associated with for example diabetic neuropathy,peripheral neuropathy, post-herpetic neuralgia, trigeminal neuralgia,lumbar or cervical radiculopathies, fibromyalgia, glossopharyngealneuralgia, reflex sympathetic dystrophy, casualgia, thalamic syndrome,nerve root avulsion, or nerve damage cause by injury resulting inperipheral and/or central sensitization such as phantom limb pain,reflex sympathetic dystrophy or postthoracotomy pain, cancer, chemicalinjury, toxins, nutritional deficiencies, or viral or bacterialinfections such as shingles or HIV, or combinations thereof. The methodsof use for compounds of this invention further include treatments inwhich the neuropathic pain is a condition secondary to metastaticinfiltration, adiposis dolorosa, burns, or central pain conditionsrelated to thalamic conditions.

As mentioned previously, the methods of the present invention may beused to treat pain that is somatic and/or visceral in nature. Forexample, somatic pain that can be treated in accordance with the methodsof the present invention include pains associated with structural orsoft tissue injury experienced during surgery, dental procedures, burns,or traumatic body injuries. Examples of visceral pain that can betreated in accordance with the methods of the present invention includethose types of pain associated with or resulting from maladies of theinternal organs such as ulcerative colitis, irritable bowel syndrome,irritable bladder, Crohn's disease, rheumatologic (arthralgias), tumors,gastritis, pancreatitis, infections of the organs, or biliary tractdisorders, or combinations thereof. One skilled in the art will alsorecognize that the pain treated according to the methods of the presentinvention may also be related to conditions of hyperalgesia, allodynia,or both. Additionally, the chronic pain may be with or withoutperipheral or central sensitization.

The compounds useful in this invention may also be used to treat acuteand/or chronic pains associated with female conditions, which may alsobe referred to as female-specific pain. Such groups of pain includethose that are encountered solely or predominately by females, includingpain associated with menstruation, ovulation, pregnancy or childbirth,miscarriage, ectopic pregnancy, retrograde menstruation, rupture of afollicular or corpus luteum cyst, irritation of the pelvic viscera,uterine fibroids, adenomyosis, endometriosis, infection andinflammation, pelvic organ ischemia, obstruction, intra-abdominaladhesions, anatomic distortion of the pelvic viscera, ovarian abscess,loss of pelvic support, tumors, pelvic congestion or referred pain fromnon-gynecological causes.

The present invention is further defined in the following Examples, inwhich all parts and percentages are by weight and degrees are Celsius,unless otherwise stated. It should be understood that these examples,while indicating preferred embodiments of the invention, are given byway of illustration only. From the above discussion and these examples,one skilled in the art can ascertain the essential characteristics ofthis invention, and without departing from the spirit and scope thereof,can make various changes and modifications of the invention to adapt itto various usages and conditions.

EXAMPLES Example 1(1RS,2SR)-1-(1H-indol-1-yl)-3-(4-methylpiperazin-1-yl)-1-phenylpropan-2-ol dihydrochloride

Step 1: A mixture of indole (2.34 g, 20 mmol) and pulverized solidpotassium hydroxide (1.12 g, 20 mmol) was stirred for 30 minutes undernitrogen at room temperature. Trans-3-phenylglycidol (3.0 g, 20 mmol) indimethylsulfoxide (1 mL) was then added and the mixture was stirred at70° C. for 2 hours until no epoxide remained. The mixture was thencooled and partitioned between water and dichloromethane. The organiclayer was separated, washed with water several times, dried overanhydrous sodium sulfate, filtered, and concentrated in vacuo. The crudeproduct was purified via Biotage chromatography (FlasH40i, silica, 10%,20%, 30% ethyl acetate/hexane) to yield 1.92 g (36%) of(2RS,3RS)-3-indol-1-yl-3-phenyl-propane-1,2-diol as an oil. ¹HNMR(DMSO): δ3.27 (m, 2H, CH₂OH), δ4.45 (m, 1H, CHOH), δ4.80 (t, 1H, CH₂OH),δ5.20 (d, 1H, CHOH), δ5.60 (d, 1H, CHPh); MS (ESI) m/z 268 ([M+H]⁺).

Step 2: A solution of (2RS,3RS)-3-indol-1-yl-3-phenyl-propane-1,2-diol(1.83 g, 6.8 mmol) and p-toluenesulfonyl chloride (1.31 g, 6.8 mmol) inanhydrous pyridine (10 mL) was stirred at room temperature undernitrogen for 15 hours. The mixture was then diluted with water (10 mL),quenched with a 2N aqueous solution of hydrochloric acid in an ice/waterbath until the solution was pH=3, and extracted with dichloromethane.The organic layer was washed with water again, dried over anhydroussodium sulfate, filtered, and concentrated. The residue was purified viaBiotage chromatography (FlasH40i, silica, 10%, 25% EtOAc/hexane) toyield 1.98 g (69%) of (2RS,3RS)-toluene-4-sulfonic acid2-hydroxy-3-indol-1-yl-3-phenyl-propyl ester as a white solid. ¹HNMR(DMSO): δ3.70 and δ3.85 (dd and dd, 2H, CH₂OTs), δ4.80 (m, 1H, CHOH),δ5.52 (d, 1H, CHPh), δ5.82 (d, 1H, CHOH); MS (ESI) m/z 422 ([M+H]⁺).

Step 3: A mixture of (2RS,3RS)-toluene-4-sulfonic acid2-hydroxy-3-indol-1-yl-3-phenyl-propyl ester (0.185 g, 0.4 mmol),1-methyl piperazine (0.05 mL, 0.4 mmol) and potassium carbonate (0.07 g,0.44 mmol) in acetonitrile (10 mL) was stirred at reflux under nitrogenfor 24 hours. After cooling, the mixture was filtered and the filtratewas concentrated and purified via Biotage chromatography (5%methanol/dichloromethane) to give a white solid of(1RS,2SR)-1-(1H-indol-1-yl)-3-(4-methylpiperazin-1-yl)-1-phenylpropan-2-ol.The free base was dissolved in a minimum amount of ethanol and treatedwith a 1N ethereal solution of hydrochloric acid until the solution waspH=3 followed by diethyl ether. The product was then crystallized byadding a minimum amount of hexane to afford the titled compound,(1RS,2SR)-1-(1H-indol-1-yl)-3-(4-methylpiperazin-1-yl)-1-phenylpropan-2-oldihydrochloride as an off-white solid. MS m/z 350 ([M+H]⁺); HRMS: calcdfor C₂₂H₂₇N_(3O)+H+, 350.22269; found (ESI, [M+H]+), 350.2228.

Example 2(1RS,2SR)-1-(2,3-dihydro-4H-1,4-benzoxazin-4-yl)-3-(methylamino)-1-phenylpropan-2-oldihydrochloride

A mixture of 3,4-dihydro-2H-benzo[1,4]oxazine (2.027 g 15.00 mmol) andtrans-ethyl-3-phenylglycidate (2.883 g, 15.00 mmol) was stirred at 135°C. for 12 hours. After cooling, the viscous liquid was purified viaBiotage Horizon (FLASH 40 M, silica, 10%, 20%, 30% EtOAc/hexane) andrecrystallized (minimal warm chloroform/hexane/−20° C.) to yield 4.261 g(87%) ethyl(2RS,3RS)-3-(2,3-dihydro-4H-1,4-benzoxazin-4-yl)-2-hydroxy-3-phenylpropanoateas a white solid. MS (ESI) m/z 328.0 ([M+H]⁺).

A mixture of ethyl(2RS,3RS)-3-(2,3-dihydro-4H-1,4-benzoxazin-4-yl)-2-hydroxy-3-phenylpropanoate(283 mg, 0.864 mmol) and ethanolic methylamine solution (5 mL, 33% inethanol) was stirred at 70° C. in a sealed tube for 5 hours. Aftercooling, all volatiles were removed under reduced pressure. Theresulting yellow solid was purified via Biotage Horizon (FLASH 12 S,silica, 20%, 35%, 50% EtOAc/hexane) to yield 235 mg (87%)(2RS,3RS)-3-(2,3-dihydro-4H-1,4-benzoxazin-4-yl)-2-hydroxy-N-methyl-3phenylpropanamide as a white solid. MS (ESI) m/z 311.0 ([M−H]⁻).

A solution of(2RS,3RS)-3-(2,3-dihydro-4H-1,4-benzoxazin-4-yl)-2-hydroxy-N-methyl-3phenylpropanamide (216 mg, 0.692 mmol) in dry tetrahydrofuran (3 mL)under nitrogen was treated dropwise with a solution of borane (1.0 M intetrahydrofuran, 3.50 mL, 3.50 mmol), and the resulting solution wasstirred at 70° C. for 2 hours. After cooling in an ice bath, thereaction mixture was treated with a 2N aqueous solution of hydrochloricacid (1 mL), and the resulting mixture was heated at 50° C. for 30minutes. Tetrahydrofuran was removed under reduced pressure, and theaqueous residue was dissolved in water (5 mL) and washed with diethylether (10 mL). The aqueous layer was made alkaline with solid potassiumcarbonate and extracted with ethyl acetate (2×10 mL). The combinedorganic extracts were washed with brine, dried (sodium sulfate) andconcentrated under reduced pressure to yield 202 mg (98%)(1RS,2SR)-1-(2,3-dihydro-4H-1,4-benzoxazin-4-yl)-3-(methylamino)-1-phenylpropan-2-olas a colorless oil. This oil was dissolved in ethanol (1 mL) and treatedwith a solution of hydrochloric acid (0.5 mL, 4M in 1,4-dioxane). Allvolatiles were again removed under reduced pressure. The resulting whitesolid was recrystallized (minimal warm ethanol/ethyl ether/−20° C.) toyield 105 mg (41%)(1RS,2SR)-1-(2,3-dihydro-4H-1,4-benzoxazin-4-yl)-3-(methylamino)-1-phenylpropan-2-oldihydrochloride as a white solid. MS (ESI) m/z 299.0 ([M+H]⁺); HRMS:calcd for C₁₈H₂₂N₂O₂+H+, 299.17540; found (ESI, [M+H]⁺), 299.1755.

Example 3(1S,2R)-1-(3-chlorophenyl)-1-(1H-indol-1-yl)-3-(methylamino)propan-2-olhydrochloride

Step 1: A suspension of sodium hydride (60% in mineral oil, 4.0 g, 100mmol) in tetrahydrofuran (600 mL) was treated dropwise with diethylethoxycarbonylmethylphosphonate (20 mL, 100 mmol) at 23° C. After 1 hours,3-chlorobenzaldehyde (9.3 mL, 82 mmol) was added. After an additional1 hour, the reaction was quenched with water (20 mL) and concentratedunder vacuum to remove tetrahydrofuran. The residue was taken up inethyl acetate (300 mL), washed with water (5×300 mL) and brine (1×300mL), dried (magnesium sulfate) and concentrated under vacuum to provide(2E)-3-(3-chlorophenyl)-acrylic acid ethyl ester (18 g, quantitative) asa clear, pale yellow oil. MS (ESI) m/z 210 ([M+H]⁺).

Step 2: (2E)-3-(3-Chlorophenyl)-acrylic acid ethyl ester (17.6 g, 82mmol) was dissolved in dry dichloromethane (300 mL), cooled to −78° C.and treated with a solution of di-iso-butylaluminum hydride (1.0 Msolution in hexane, 250 mL, 250 mmol) over 20 minutes. After 1.5 hourstotal, the reaction was quenched with methanol (75 mL) at −78° C.,warmed to 23° C. and treated with a saturated aqueous solution ofpotassium sodium tartrate (300 mL). The aqueous phase was separated andextracted with dichloromethane (2×300 mL). The combined extracts werewashed with a saturated aqueous solution of sodium tartrate (450 mL),dried (sodium sulfate) and concentrated under vacuum to provide a cloudyyellow oil (14.6 g) that was pre-adsorbed on silica gel (25 g). Flashcolumn chromatography (silica 250 g, 10%, 20% ethyl acetate/hexanes)provided (2E)-3-(3-chlorophenyl)prop-2-en-1-ol (12.4 g, 90%) as a clear,colorless oil. MS (ESI) m/z 151 ([M+H—H₂O]⁺).

Step 3: In an analogous manner to EXAMPLE 10, step 4,[(2R,3R)-3-(3-chlorophenyl)oxiran-2-yl]methanol was prepared from(2E)-3-(3-chlorophenyl)prop-2-en-1-ol. MS (ESI) m/z 167 ([M+H—H₂O]⁺).

Step 4 (Method A): In an analogous manner to EXAMPLE 10, step 5,(2S,3S)-3-(3-chlorophenyl)-3-(1H-indol-1-yl)propane-1,2-diol wasprepared from 1H-indole and[(2R,3R)-3-(3-chlorophenyl)oxiran-2-yl]methanol. MS (ES) m/z 302([M+H]⁺).

Step 4a (Method B): [(2R,3R)-3-(3-chlorophenyl)oxiran-2-yl]methanol (4.8g, 26 mmol) and indoline (d 1.063, 2.9 mL, 26 mmol) were heated neat at135° C. in a sealed flask. After 1.5 hours, the cooled mixture waspre-adsorbed on silica gel (25 g). Flash column chromatography (silica375 g, 20%, 40%, 80% ethyl acetate/hexanes) provided(2S,3S)-3-(3-chlorophenyl)-3-(2,3-dihydro-1H-indol-1-yl)propane-1,2-diol(5.8 g, 73%) as a white solid. MS (ES) m/z 304 ([M+H]⁺).

Step 4b (Method B): A solution of(2S,3S)-3-(3-chlorophenyl)-3-(2,3-dihydro-1H-indol-1-yl)propane-1,2-diol(5.8 g, 19 mmol) in ca. 1:1 (v/v) toluene-dichloromethane (200 mL) wastreated with a solution of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone(4.4 g, 19 mmol) in toluene (100 mL) at 0° C. After 30 minutes, themixture was diluted with ethyl acetate (1 L) and washed with 5% aqueoussodium carbonate (4×1 L), water (1 L) and brine (1 L), dried (magnesiumsulfate) and concentrated under vacuum to give a dark oil (5.4 g) thatwas pre-adsorbed on silica gel (15 g). Flash column chromatography(silica 235 g, 20%, 40% ethyl acetate/hexanes) provided(2S,3S)-3-(3-chlorophenyl)-3-(1H-indol-1-yl)propane-1,2-diol, (4.7 g,82%) as a cloudy yellow oil. MS (ES) m/z 302 ([M+H]⁺).

Step 5: In an analogous manner to EXAMPLE 1, step 2,(2S,3S)-toluene-4-sulfonic acid3-(3-chlorophenyl)-2-hydroxy-3-indol-1-yl-propyl ester was prepared from(2S,3S)-3-(3-chlorophenyl)-3-(1H-indol-1-yl)propane-1,2-diol. MS (ES)m/z 456 ([M+H]⁺).

Step 6: (2S,3S)-Toluene-4-sulfonic acid3-(3-chlorophenyl)-2-hydroxy-3-indol-1-yl-propyl ester (0.60 g, 1.2mmol) was treated with a solution of methylamine in methanol (2.0 M, 3mL, 6 mmol) and the solution was stirred at 23° C. for 18 hours. At thistime, the solution was concentrated under vacuum and dissolved indiethyl ether (50 mL). The organic solution was washed with a 1 Naqueous solution of sodium hydroxide (50 mL), water (50 mL) and brine(50 mL), dried (sodium sulfate) and concentrated under vacuum to providean orange foam (0.30 g) that was purified by reverse phase HPLC (90:10water-acetonitrile to 50:50 water-acetonitrile containing 0.1%trifluoroacetic acid @ 20 mL/min). The product fractions wereconcentrated under vacuum to remove acetonitrile and the aqueoussolution was basified with a 2N aqueous solution of ammonium hydroxide.The resulting milky suspension was extracted with ethyl acetate (200 mL)and the organic phase was washed with water (200 mL) and brine (100 mL),dried (sodium sulfate) and concentrated under vacuum. The residue wasdissolved in absolute ethanol (4 mL), treated with a 4 M hydrochloricacid in 1,4-dioxane (1.3 eq) and stirred for 10 minutes. The solutionwas concentrated under vacuum, then dissolved in absolute ethanol (3 mL)and left standing at 23° C. overnight. Vacuum filtration provided(1S,2R)-1-(3-chlorophenyl)-1-(1H-indol-1-yl)-3-(methylamino)propan-2-olhydrochloride (62 mg, 5% for 3 steps) as a white crystalline solid. HRMScalcd for C₁₈H₁₉ClN₂O+H⁺, 315.12587; found (ESI) 315.1267 ([M+H]⁺).

Example 4(1SR,2RS)-3-(methylamino)-1-(4-methyl-3,4-dihydroquinoxalin-1(2H)-yl)-1-phenylpropan-2-olhydrochloride

Step 1: In an analogous manner to EXAMPLE 7, step 3,3-phenylglycidol wasprepared from cinnamyl alcohol as a white solid. MS (ES) m/z 151.1([M+H]⁺).

Step 2: In an analogous manner to EXAMPLE 6, step 4,(2SR,3SR)-3-(4-methyl-3,4-dihydroquinoxalin-1(2H)-yl)-3-phenylpropane-1,2-diolwas prepared from 1-methyl-1,2,3,4-tetrahydroquinoxaline¹ and3-phenylglycidol as a viscous colorless oil. MS (ES) m/z 299.0 ([M+H]⁺);HRMS: calcd for C₁₈H₂₂N₂O₂+H⁺, 299.1760; found (ESI, [M+H]⁺), 299.1739.¹Cavagnol, J. C.; Wiselogle, F. Y. J. Am. Chem. Soc. 1947, 69, 795-799.

Step 3: In an analogous manner to EXAMPLE 6, step 6,(1SR,2RS)-3-(methylamino)-1-(4-methyl-3,4-dihydroquinoxalin-1(2H)-yl)-1-phenylpropan-2-olhydrochloride was prepared from(2SR,3SR)-3-(4-methyl-3,4-dihydroquinoxalin-1(2H)-yl)-3-phenylpropane-1,2-diolas a white powder. MS (ES) m/z 312.0 ([M+H]⁺); HRMS: calcd forC₁₉H₂₅N₃O+H⁺, 312.2076; found (ESI, [M+H]⁺), 312.2065.

Example 5(1SR,2RS)-3-(methylamino)-1-phenyl-1-[4-(2,2,2-trifluoroethyl)-3,4-dihydroquinoxalin-1(2H)-yl]propan-2-olhydrochloride

Compound 1-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroquinoxaline wasobtained as a white powder side product of the reduction reaction ofquinoxaline to 1,2,3,4-tetrahydroquinoxaline using sodium borohydride intrifluoroacetic acid.² MS (ES) m/z 217.1 ([M+H]⁺). ² Bugle, R. C.;Osteryoung, R. A. J. Org. Chem. 1979, 44, 1719-1720.

In an analogous manner to EXAMPLE 6, step 4,(2SR,3SR)-3-(4-(2,2,2-trifluoroethyl)-3,4-dihydroquinoxalin-1(2H)-yl)-3-phenylpropane-1,2-diolwas prepared from 1-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroquinoxalineand 3-phenylglycidol (EXAMPLE 4, step 1) as a viscous colorless oil.

In an analogous manner to EXAMPLE 6, step 6,(1SR,2RS)-3-(methylamino)-1-phenyl-1-[4-(2,2,2-trifluoroethyl)-3,4-dihydroquinoxalin-1(2H)-yl]propan-2-olhydrochloride was prepared from(2SR,3SR)-3-(4-(2,2,2-trifluoroethyl)-3,4-dihydroquinoxalin-1(2H)-yl)-3-phenylpropane-1,2-diolas a white powder. MS (ES) m/z 380.0 ([M+H]⁺); HRMS: calcd forC₂₀H₂₄F₃N₃O+H⁺, 380.1950; found (ESI, [M+H]⁺), 380.1934.

Example 6(1S,2R)-1-(3-fluorophenyl)-1-(1H-indol-1-yl)-3-(methylamino)propan-2-olhydrochloride

Step 1: To a mixture of trans-3-fluorocinnamic acid (50 g, 300 mmol) andiodomethane (300 mL) in acetone (1 L) was added portionwise cesiumcarbonate (147 g, 450 mmol, 1.5 equiv.), and the mixture was heated at65° C. for 1.5 hours in a sealed reaction vessel. Upon cooling to roomtemperature, the reaction mixture was diluted with ethyl acetate (1 L),filtered through a pad of silica gel, and concentrated to give 47.33 g(87%) of trans-3-fluorocinnamic acid methyl ester as a colorless oil. MS(ES) m/z 180.0 (M⁺).

Step 2: To a solution of trans-3-fluorocinnamic acid methyl ester (69.61g, 386 mmol) in dry dichloromethane (1 L) at −78° C. under nitrogen wasadded dropwise diisobutylaluminum hydride (neat, 172 mL, 965 mmol, 2.5equiv.) via an addition funnel. After the addition was complete, thereaction mixture was allowed to warm to −30° C. and stirred for anadditional 1 hour, then quenched with methanol (150 mL). Upon warming toroom temperature, the reaction mixture was treated with saturatedaqueous solution of sodium/potassium tartrate (300 mL) and stirred for30 minutes. The organic layer was washed sequentially with 1N aqueoushydrochloric acid solution, saturated aqueous sodium bicarbonatesolution, brine, and dried (anhydrous sodium sulfate). The crude oil waspurified by silica gel chromatography (0-50% ethyl acetate:hexane) togive 53.07 g (90%) of trans-3-fluorocinnamyl alcohol as a colorless oil.MS (ES) m/z 152.1 (M⁺).

Step 3: An oven-dried, 3-neck, 2-L round bottom flask fitted with twooven-dried addition funnels and a rubber septum was charged withdiisopropyl D-tartrate (11.55 g, 49.3 mmol, 0.30 equiv.), 4 Å powdered,activated molecular sieves (40 g) and dry dichloromethane (800 mL) undernitrogen. After being cooled to −25° C., to the reaction mixture wasadded titanium isopropoxide (9.6 mL, 33 mmol, 0.20 equiv.) slowly via ahypodermic syringe. After stirring for 10 minutes, anhydrous t-butylhydroperoxide (5.5 M in decane, 75.0 mL, 413 mmol, 2.5 equiv.) was addedat a moderate rate via an addition funnel. The resulting mixture wasstirred at −25° C. for 30 minutes. trans-3-Fluorocinnamyl alcohol (25.0g, 164 mmol) in dry dichloromethane (50 mL) was added dropwise via anaddition funnel while maintaining the temperature at −25° C. After theaddition, the reaction mixture was stirred at −25° C. for 1 hour and at−20° C. for another 3 hours. After the reaction was complete, cooledaqueous sodium hydroxide solution (30%, 20 mL) saturated with sodiumchloride was added slowly at −20° C. After diethyl ether (150 mL) wasadded, the cold bath was removed and the mixture was allowed to warm to˜5° C. and stirred for 1 hour. Magnesium sulfate (anhydrous, 50 g) wasadded and the mixture was stirred for 20 minutes, then filtered througha pad of silica gel, and washed with ether (300 mL). The filtrate wasconcentrated and toluene was used to azeotropically remove excesst-butyl hydroperoxide. The residual oil was purified on silica gel(0-30% ethyl acetate:hexane) to give 24.80 g (90%) of[(2R,3R)-3-(3-fluorophenyl)oxiran-2-yl]methanol as a viscous, colorlessoil. Percent ee: >96.5%. MS (ESI) m/z 169.1 ([M+H]⁺).

Step 4: A mixture of indoline (1.42 g, 11.89 mmol) and[(2R,3R)-3-(3-fluorophenyl)oxiran-2-yl]methanol (2.0 g, 11.89 mmol) washeated at 125° C. for 5 hours in a sealed reaction vial. Upon cooling,the crude product was dissolved in ethyl acetate, absorbed on Fluorocil,and purified by Biotage chromatography (FlasH40i, silica, 0-55%EtOAc/hexane) to give 2.55 g (75%) of(2S,3S)-3-(2,3-dihydro-1H-indol-1-yl)-3-(3-fluorophenyl)propane-1,2-diolas a colorless oil. MS (ESI) m/z 288.1 ([M+H]⁺).

Step 5: A mixture of(2S,3S)-3-(2,3-dihydro-1H-indol-1-yl)-3-(3-fluorophenyl)propane-1,2-diol(2.00 g, 6.96 mmol) and activated manganese dioxide (20.0 g, 230 mmol)in dichloromethane (30 mL) was stirred at 20° C. for 3 hours. Themixture was diluted with ethyl acetate (15 mL), filtered through a padof silica gel, and concentrated. The crude product was purified byBiotage chromatography (FlasH40i, silica, 0-70% EtOAc/hexane) to give1.40 g (71%) of(2S,3S)-3-(3-fluorophenyl)-3-(1H-indol-1-yl)propane-1,2-diol as acolorless oil. MS (ESI) m/z 286.0 ([M+H]⁺). HRMS: calcd forC₁₇H₁₆FNO₂+H⁺, 286.1238; found (ESI, [M+H]⁺), 286.1239.

Step 6: To a solution of(2S,3S)-3-(2,3-dihydro-1H-indol-1-yl)-3-(3-fluorophenyl)propane-1,2-diol(452 mg, 1.586 mmol) in dichloromethane (3 mL) under nitrogen was addedtriethylamine (1.1 mL, 7.93 mmol). The mixture was cooled to 0° C., andpara-toluenesulfonyl chloride (423 mg, 2.22 mmol) was added portionwise.The reaction mixture was stirred at 0° C. for 1 hour and stored at 0° C.overnight. Methylamine in absolute ethanol (8 M, 5 mL, 40 mmol) wasadded and the reaction mixture was sealed, and stirred overnight whilewarming to room temperature. All volatiles were removed under reducedpressure. The oil residue was dissolved in dichloromethane (20 mL),washed with aqueous potassium carbonate (5 mL), dried (anhydrous sodiumsulfate), and concentrated. Purification by Biotage chromatography(FlasH12i, silica, 0-15% MeOH/dichloromethane/0.5% triethylamine) gave(1S,2R)-1-(3-fluorophenyl)-1-(1H-indol-1-yl)-3-(methylamino)propan-2-ol,which was dissolved dichloromethane (5 mL) and treated with a 1Methereal solution of hydrochloric acid (1.9 mL, 1.9 mmol). To theresulting solution was added hexane until white powder formed, which wascollected, washed with hexane, and dried in vacuo to yield 209 mg (44%)of(1S,2R)-1-(3-fluorophenyl)-1-(1H-indol-1-yl)-3-(methylamino)propan-2-olhydrochloride as a white powder. MS (ES) m/z 299.0 ([M+H]⁺); HRMS: calcdfor C₁₈H₁₉FN₂O+H⁺, 299.1554; found (ESI, [M+H]⁺), 299.1553.

Example 7(1S,2R)-1-(1H-indol-1-yl)-3-(methylamino)-1-(2-methylphenyl)propan-2-olhydrochloride

Step 1: In an analogous manner to EXAMPLE 6, step 1,trans-2-methylcinnamic acid methyl ester was prepared fromtrans-2-methylcinnamic acid.

Step 2: In an analogous manner to EXAMPLE 6, step 2,trans-2-methylcinnamyl alcohol was prepared from trans-2-methylcinnamicacid methyl ester as a colorless oil. MS (ES) m/z 146.9 ([M−H]⁻).

Step 3: To a solution of trans-2-methylcinnamyl alcohol (1.50 g, 10.14mmol) in dichloromethane (30 mL) was added sodium carbonate (1.50 g,14.19 mmol). The mixture was cooled to 10° C. and peracetic acid (32 wt%, 2.56 mL, 12.16 mmol) was added dropwise via an addition funnel. Thereaction mixture was stirred for 3 hours while warming to roomtemperature, and quenched with saturated aqueous sodium sulfite solution(15 mL) slowly. More dichloromethane (30 mL) was added and the mixturewas extracted. The organic layer was washed with brine, dried (anhydroussodium sulfate), and concentrated. The oil residue was purified bysilica gel chromatography (10-30% EtOAc/hexane) to give 920 mg (55%) of3-(2-methylphenyl)glycidol as a colorless oil. HRMS: calcd forC₁₀H₁₂O₂+H⁺, 165.0916; found (ESI, [M+H]⁺), 165.0936.

Step 4: In an analogous manner to EXAMPLE 10, step 5,(2SR,3SR)-3-(1H-indol-1-yl)-3-(2-methylphenyl)propane-1,2-diol wasprepared from indole and 3-(2-methylphenyl)glycidol as a viscous,colorless liquid. MS (ES) m/z 282.2 ([M+H]⁺); HRMS: calcd forC₁₈H₁₉NO₂+H⁺, 282.1494; found (ESI, [M+H]⁺), 282.1499.

Step 5: In an analogous manner to EXAMPLE 6, step 6,(1SR,2RS)-1-(1H-indol-1-yl)-3-(methylamino)-1-(2-methylphenyl)propan-2-olwas prepared from(2SR,3SR)-3-(1H-indol-1-yl)-3-(2-methylphenyl)propane-1,2-diol as anoil.

Step 6: Racemic(1SR,2RS)1-(1H-indol-1-yl)-3-(methylamino)-1-(2-methylphenyl)propan-2-olwas dissolved in ethanol (20 mg/mL). The resulting solution was stackinjected onto the Supercritical Fluid Chromatography instrument at 1 mLincrements. The baseline resolved enantiomers, using the conditionsdescribed below, were collected. The enantiomeric purity of eachenantiomer was determined under similar Supercritical FluidChromatography conditions using a Chiralcel OJ-H 5u, 250 mm L×4.6 mm IDcolumn at 1.2 mL/minutes flow rate using Analytical Supercritical FluidChromatography (Berger Instruments, Inc. Newark, Del. USA).

SFC Instrument: Berger MultiGram Prep SFC (Berger Instruments, Inc.Newark, DE 19702. Column: Chiralcel OJ-H; 5 u; 250 mm L × 20 mm ID(Chiral Technologies, Inc., Exton, PA, USA) Column temperature: 35° C.SFC Modifier: 15% MeOH with 1.0% DEA/85% CO₂ Flow rate: 50 mL/min OutletPressure: 100 bar Detector: UV at 220 nm

Step 7: In an analogous manner to EXAMPLE 13, step 2,(1S,2R)-1-(1H-indol-1-yl)-3-(methylamino)-1-(2-methylphenyl)propan-2-olhydrochloride was prepared as a white solid, from(1S,2R)-1-(1H-indol-1-yl)-3-(methylamino)-1-(2-methylphenyl)propan-2-ol,which was isolated as Peak 1 of the chiral separation (step 6). Chiralpurity: 100%. MS (ESI) m/z 295.3 ([M+H]⁺); HRMS: calcd for C₁₉H₂₂N₂O+H⁺,295.1805; found (ESI, [M+H]⁺), 295.1795.

Example 8(1S,2R)-1-(6-chloro-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-1-(3,5-difluorophenyl)-3-(methylamino)propan-2-olhydrochloride

Step 1: In an analogous manner to EXAMPLE 16, step1,6-chloro-3,4-dihydro-2H-1,4-benzoxazine was prepared from6-chloro-2H-1,4-benzoxazin-3(4H)-one as a yellow solid. MS (ES) m/z170.0 ([M+H]⁺); HRMS: calcd for C₈H₈ClNO+H⁺, 170.0367; found (ESI,[M+H]⁺), 170.0365.

Step 2: In an analogous manner to EXAMPLE 6, step 4,(2S,3S)-3-(6-chloro-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-3-(3,5-difluorophenyl)propane-1,2-diolwas prepared from 6-chloro-3,4-dihydro-2H-1,4-benzoxazine and[(2R,3R)-3-(3,5-difluorophenyl)oxiran-2-yl]methanol (EXAMPLE 157, step3) as a viscous, yellowish liquid. MS (ES) m/z 356.1 ([M+H]⁺); HRMS:calcd for C₁₇H₁₆ClF₂NO₃+H⁺, 356.0860; found (ESI, [M+H]⁺), 356.0869.

Step 3: In an analogous manner to EXAMPLE 6, step 6,(1S,2R)-1-(6-chloro-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-1-(3,5-difluorophenyl)-3-(methylamino)propan-2-olhydrochloride was prepared from(2S,3S)-3-(6-chloro-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-3-(3,5-difluorophenyl)propane-1,2-diolas a white powder. MS (ES) m/z 369.1 ([M+H]⁺); HRMS: calcd forC₁₈H₁₉ClF₂N₂O₂+H⁺, 369.1176; found (ESI, [M+H]⁺), 369.1178.

Example 9(1S,2R)-1-(3-fluorophenyl)-3-(methylamino)-1-(2-methyl-2,3-dihydro-4H-1,4-benzoxazin-4-yl)propan-2-olhydrochloride

In an analogous manner to EXAMPLE 16, step1,2-methyl-3,4-dihydro-2H-1,4-benzoxazine was prepared from2-methyl-2H-1,4-benzoxazin-3(4H)-one³ as a brown oil. MS (ES) m/z 149.9([M+H]⁺). ³ Wheeler, K. W. J. Med. Pharm. Chem. 1962, 5, 1378-1383.

In an analogous manner to EXAMPLE 6, step 4,(2S,3S)-3-(3-fluorophenyl)-3-(2-methyl-2,3-dihydro-4H-1,4-benzoxazin-4-yl)propane-1,2-diolwas prepared from 2-methyl-3,4-dihydro-2H-1,4-benzoxazine and[(2R,3R)-3-(3-fluorophenyl)oxiran-2-yl]methanol (EXAMPLE 6, step 3) as aviscous, brown liquid. MS (ES) m/z 318.2 ([M+H]⁺); HRMS: calcd forC₁₈H₂₀FNO₃+H⁺, 318.1500; found (ESI, [M+H]⁺), 318.1513.

In an analogous manner to EXAMPLE 6, step 6,(1S,2R)-1-(3-fluorophenyl)-3-(methylamino)-1-(2-methyl-2,3-dihydro-4H-1,4-benzoxazin-4-yl)propan-2-olhydrochloride was prepared from(2S,3S)-3-(3-fluorophenyl)-3-(2-methyl-2,3-dihydro-4H-1,4-benzoxazin-4-yl)propane-1,2-diolas a white powder. MS (ES) m/z 331.0 ([M+H]⁺); HRMS: calcd forC₁₉H₂₃FN₂O₂+H⁺, 331.1816; found (ESI, [M+H]⁺), 331.1804.

Example 10(1S,2R)-1-(5-fluoro-3-methyl-1H-indol-1-yl)-3-(methylamino)-1-phenylpropan-2-olhydrochloride

Step 1: To a mixture of 4-fluoro-phenylamine (9 g, 81 mmol),concentrated hydrochloric acid (20.4 mL), and water (35.1 mL) was addedsodium nitrite (6.3 g, 89.1 mmol) dissolved in water (7.8 mL). In aseparate flask ethyl 2-ethylacetoacetate (14.4 g, 89.1 mmol) in ethanol(63.6 mL) at 0° C. was treated with potassium hydroxide (5.1 g, 89.1mmol) in water (7.5 mL) and ice and the above solution added. The pH ofthe reaction was adjusted to 5-6 and the reaction stirred at 0° C. for 3hours and then stored in the freezer overnight. The reaction was thenextracted with ethyl acetate (100 mL) and the organics washed withsaturated brine solution (100 mL), dried with anhydrous magnesiumsulfate. Most of the solvent was removed in vacuo before it was addeddropwise to a 14.5% ethanolic solution of hydrochloric acid (70 mL) at78° C. Heating was continued for 2 hours. The solvent was removed invacuo and the residue treated with dichloromethane (300 mL) and water(100 mL). The organic layer was washed with saturated sodium chloride(200 mL), dried over sodium sulfate and concentrated in vacuo.Purification on a short wash column (silica gel, 25% ethylacetate/hexane) gave ethyl 5-fluoro-3-methyl-1H-indole-2-carboxylate asa white solid. MS (ES) m/z 220.0

Step 2: Ethyl 5-fluoro-3-methyl-1H-indole-2-carboxylate (8.3 g, 37.5mmol) and potassium hydroxide (6.3 g, 112.5 mmol) in a mixture ofethanol (20 mL) and water (15 mL) was heated at reflux for 1 hour. Thevolume was reduced to 10 mL under reduced pressure and the solutionbrought to an acidic pH with a 3N aqueous solution of hydrochloric acid.The resulting precipitate was filtered, washed with water (100 mL) anddried in vacuo at 80° C. overnight to afford5-fluoro-3-methyl-1H-indole-2-carboxylic acid as a white solid. MS (ES)m/z 192.0

Step 3: 5-fluoro-3-methyl-1H-indole-2-carboxylic acid (8.49 g, 43.9mmol) and copper metal (0.35 g, 5.5 mmol) in distilled quinoline (22 mL)was heated to reflux for 3 hours. The copper powder was filtered off andthe filtrate was brought to pH 3 at 0° C. with a 6N aqueous solution ofhydrochloric acid. The solution was extracted with ether (200 mL) andthe organics washed with saturated sodium chloride (200 mL), dried overmagnesium sulfate and concentrated in vacuo to give5-fluoro-3-methyl-1H-indole as a brown solid. MS (ES) m/z 150.0.

Step 4: To a solution of diisopropyl D-tartrate (6 mL, 28 mmol) inmethylene chloride (800 mL) at −10° C. under nitrogen was added 4Amolecular sieves (15 g), titanium isopropoxide (5.9 mL, 20 mmol), andcinnamyl alcohol (27 g, 200 mmol). The mixture was allowed to age for 40minutes at −10° C., after which time it was cooled to −20° C., andtreated in a dropwise fashion with a solution of tert-butylhydroperoxide (TBHP, ˜450 mmol) in isooctane. After 18 hours at −30 to−15° C., the reaction mixture was treated with a 30% aqueous solution ofsodium hydroxide (5 mL) and diethyl ether (100 mL). The cold bath wasremoved and the mixture was allowed to warm to ˜10° C. Magnesium sulfate(anhydrous, 15 g) was added and the mixture was stirred for 20 minutes.After the solids settled, the solution was filtered through a pad ofsilica gel, and washed with ether (50 mL). The filtrate was concentratedin vacuo and toluene was added to azeotropically remove the unreactedTBHP. The residue was then purified using a silica gel column(hexane:ethyl acetate/3:1) and the purified product was crystallizedfrom hexane/ethyl acetate to yield [(2R,3R)-3-phenyloxiran-2-yl]methanolas white crystal (18 g, 60%, 98.2% ee). MS (ESI) m/z 151.

Step 5: A mixture of 5-fluoro-3-methyl-1H-indole (2.91 g, 19.5 mmol) andpotassium hydride 50% dispersion in mineral oil (2.8 g, 35.1 mmol) indichloromethane (40 mL) was stirred for 10 minutes under nitrogen atroom temperature. A solution of [(2R,3R)-3-phenyloxiran-2-yl]methanol(2.0 g, 13.0 mmol) and titanium isopropoxide (4.3 mL, 14.3 mmol) indichloromethane (10 mL) was then added and the mixture was stirred atroom temperature for 12 hours. After disappearance of the epoxide, themixture was partitioned between a 1N aqueous solution of hydrochloricacid (50 mL) and ethyl acetate (50 mL). The organic layer was separated,washed with saturated sodium bicarbonate (50 mL), dried over anhydroussodium sulfate, filtered, and concentrated in vacuo. The crude productwas purified via Biotage chromatography (FlasH40i, silica, 60% ethylacetate/hexane) to give(2S,3S)-3-(5-fluoro-3-methyl-1H-indol-1-yl)-3-phenylpropane-1,2-diol. MS(ESI) m/z 300

Step 6: A solution of(2S,3S)-3-(5-fluoro-3-methyl-1H-indol-1-yl)-3-phenylpropane-1,2-diol(1.03 g, 3.4 mmol) and p-toluenesulfonyl chloride (0.78 g, 4.1 mmol) inanhydrous pyridine (11 ml) was stirred at room temperature undernitrogen for 12 hours. The reaction was poured into a 1N aqueoussolution of hydrochloric acid (50 mL) and extracted with ethyl acetate(50 mL). The organics were dried over anhydrous sodium sulfate,filtered, and concentrated to give (2S,3S)-toluene-4-sulfonic acid3-(5-fluoro-3-methyl-indol-1-yl)-2-hydroxy-3-phenyl-propyl ester. Theproduct was used in the next step without further purification. To asolution of toluene-4-sulfonic acid3-(5-fluoro-3-methyl-indol-1-yl)-2-hydroxy-3-phenyl-propyl ester (1.6 g,3.4 mmol) in methanol (10 mL) was added a 2N solution of methylamine inmethanol (8.6 mL, 17 mmol) and the reaction stirred for 12 hours. Uponcompletion, the reaction was partitioned between saturated sodiumbicarbonate (50 mL) and ethyl acetate (50 mL). The organic layer wasseparated, dried over anhydrous sodium sulfate, filtered, andconcentrated in vacuo. The crude product was purified via Biotagechromatography (FlasH40i, silica, 20% MeOH/dichloromethane) to give(1S,2R)-1-(5-fluoro-3-methyl-1H-indol-1-yl)-3-(methylamino)-1-phenylpropan-2-olas a clear oil. The free base was dissolved in a minimum amount ofethanol and treated with a 2N ethereal solution of hydrochloric acid andstirred for 1 hour. The ethanol was removed in vacuo and the clear oilwas triturated with ether/dichloromethane to give(1S,2R)-1-(5-fluoro-3-methyl-1H-indol-1-yl)-3-(methylamino)-1-phenylpropan-2-olhydrochloride as a white solid. MS (ESI) m/z 313

Example 11(1RS,2SR)-1-(6-chloro-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-3-(methylamino)-1-phenylpropan-2-olhydrochloride

In an analogous manner to EXAMPLE 3, step 1, ethyl(2RS,3RS)-3-(6-chloro-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-2-hydroxy-3-phenylpropanoatewas prepared from 6-chloro-3,4-dihydro-2H-1,4-benzoxazine (EXAMPLE 8,step 1) and trans-ethyl-3-phenylglycidate as a viscous, yellow liquid.MS (ESI) m/z 362.0 ([M+H]⁺); HRMS: calcd for C₁₉H₂₀ClNO₄ ⁺H⁺, 362.1154;found (ESI, [M+H]⁺), 362.1150.

In an analogous manner to EXAMPLE 3, step 2,(2RS,3RS)-3-(6-chloro-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-2-hydroxy-N-methyl-3-phenylpropanamidewas prepared from ethyl(2RS,3RS)-3-(6-chloro-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-2-hydroxy-3-phenylpropanoate as white needles. MS (ESI) m/z 344.9 ([M−H]⁻); HRMS: calcdfor C₁₈H₁₉ClN₂O₃+H⁺, 347.1157; found (ESI, [M+H]⁺), 347.1150.

In an analogous manner to EXAMPLE 3, step 3,(1RS,2SR)-1-(6-chloro-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-3-(methylamino)-1-phenylpropan-2-olhydrochloride was prepared from(2RS,3RS)-3-(6-chloro-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-2-hydroxy-N-methyl-3-phenylpropanamideas a white powder. MS (ESI) m/z 333.1 ([M+H]⁺); HRMS: calcd forC₁₈H₂₁ClN₂O₂+H⁺, 333.1370; found (ESI, [M+H]⁺), 333.1381.

Example 12(1RS,2SR)-3-(methylamino)-1-(6-methyl-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-1-phenylpropan-2-olhydrochloride

In an analogous manner to EXAMPLE 16, step1,6-methyl-3,4-dihydro-2H-1,4-benzoxazine was prepared from6-methyl-2H-1,4-benzoxazin-3(4H)-one as a yellow oil. MS (ES) m/z 150.0([M+H]⁺); HRMS: calcd for C₉H₁₁NO+H⁺, 150.0919; found (ESI, [M+H]⁺),150.0924.

In an analogous manner to EXAMPLE 3, step 1, ethyl(2RS,3RS)-2-hydroxy-3-(6-methyl-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-3-phenylpropanoatewas prepared from 6-methyl-3,4-dihydro-2H-1,4-benzoxazine andtrans-ethyl-3-phenylglycidate as a viscous, yellow liquid. MS (ESI) m/z342.0 ([M+H]⁺); HRMS: calcd for C₂₀H₂₃NO₄ ⁺H⁺, 342.1700; found (ESI,[M+H]⁺), 342.1683.

In an analogous manner to EXAMPLE 3, step 2,(2RS,3RS)-2-hydroxy-N-methyl-3-(6-methyl-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-3-phenylpropanamidewas prepared from ethyl(2RS,3RS)-2-hydroxy-3-(6-methyl-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-3-phenylpropanoate as a white powder. MS (ESI) m/z 325.0 ([M−H]⁻); HRMS: calcdfor C₁₉H₂₂N₂O₃+H⁺, 327.1703; found (ESI, [M+H]⁺), 327.1703.

In an analogous manner to EXAMPLE 3, step 3,(1RS,2SR)-3-(methylamino)-1-(6-methyl-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-1-phenylpropan-2-olhydrochloride was prepared from(2RS,3RS)-2-hydroxy-N-methyl-3-(6-methyl-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-3-phenylpropanamideas a white powder. MS (ESI) m/z 313.0 ([M+H]⁺); HRMS: calcd forC₁₉H₂₄N₂O₂+H⁺, 313.1911; found (ESI, [M+H]⁺), 313.1908.

Example 13(1S,2R)-1-(6-chloro-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-3-(methylamino)-1-phenylpropan-2-olhydrochloride

Step 1: Racemic(1RS,2SR)-1-(6-chloro-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-3-(methylamino)-1-phenylpropan-2-ol(EXAMPLE 11) was dissolved in methanol. The resulting solution wasinjected onto the Supercritical Fluid Chromatography instrument. Thebaseline resolved enantiomers, using the conditions described below,were collected. The enantiomeric purity of each enantiomer wasdetermined under the same Supercritical Fluid Chromatography conditionsusing a Chiralpak AD-H 5u, 250 mm×4.6 mm ID column at 2.0 mL/minutesflow rate using Analytical Supercritical Fluid Chromatography (BergerInstruments, Inc. Newark, Del. USA).

SFC Instrument: Berger MultiGram Prep SFC (Berger Instruments, Inc.Newark, DE 19702. Column: Chiralpak AD-H; 5 u; 250 mm L × 20 mm ID(Chiral Technologies, Inc, Exton, PA, USA) Column temperature: 35° C.SFC Modifier: 40% MeOH with 0.5% DEA Flow rate: 50 mL/min OutletPressure: 100 bar Detector: UV at 266 nm

Step 2: A solution of(1S,2R)-1-(6-chloro-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-3-(methylamino)-1-phenylpropan-2-ol,isolated as Peak 1, (58 mg, 0.17 mmol) in dichloromethane (3 mL) wastreated with an ethereal solution of hydrochloric acid (1 M, 0.2 mL, 0.2mmol). To the resulting solution was added hexane until white powderformed, which was collected, washed with hexane, and dried in vacuo toyield 62 mg (45%) of(1S,2R)-1-(6-chloro-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-3-(methylamino)-1-phenylpropan-2-olhydrochloride. Chiral purity: >99.9%. MS (ESI) m/z 333.0 ([M+H]⁺); HRMS:calcd for C₁₈H₂₁ClN₂O₂+H⁺, 333.1370; found (ESI, [M+H]⁺), 333.1372.

Example 14(1R,2S)-1-(6-chloro-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-3-(methylamino)-1-phenylpropan-2-olhydrochloride

In an analogous manner to EXAMPLE 13, step 2,(1R,2S)-1-(6-chloro-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-3-(methylamino)-1-phenylpropan-2-olhydrochloride was prepared from(1R,2S)-1-(6-chloro-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-3-(methylamino)-1-phenylpropan-2-olwhich was isolated as Peak 2 of the chiral separation (EXAMPLE 13, step1). Chiral purity: >99.9%. MS (ESI) m/z 333.0 ([M+H]⁺); HRMS: calcd forC₁₈H₂₁ClN₂O₂+H⁺, 333.1370; found (ESI, [M+H]⁺), 333.1374.

Example 15(1S,2R)-1-(6-chloro-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-1-(3-fluorophenyl)-3-(methylamino)propan-2-olhydrochloride

In an analogous manner to EXAMPLE 6, step 4,(2S,3S)-3-(6-chloro-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-3-(3-fluorophenyl)propane-1,2-diolwas prepared from 6-chloro-3,4-dihydro-2H-1,4-benzoxazine (EXAMPLE 8,step 1) and [(2R,3R)-3-(3-fluorophenyl)oxiran-2-yl]methanol (EXAMPLE 6,step 3) as a viscous, yellowish liquid. MS (ES) m/z 335.8 ([M−H]⁻);HRMS: calcd for C₂₀H₂₂FNO₂+H⁺, 338.0959; found (ESI, [M+H]⁺), 338.0959.

In an analogous manner to EXAMPLE 6, step 6,(1S,2R)-1-(6-chloro-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-1-(3-fluorophenyl)-3-(methylamino)propan-2-olhydrochloride was prepared from(2S,3S)-3-(6-chloro-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-3-(3-fluorophenyl)propane-1,2-diolas a white powder. MS (ES) m/z 351.0 ([M+H]⁺); HRMS: calcd forC₁₈H₂₀ClFN₂O₂+H⁺, 351.1276; found (ESI, [M+H]⁺), 351.1276.

Example 16(1S,2R)-1-(2,2-dimethyl-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-1-(3-fluorophenyl)-3-(methylamino)propan-2-olhydrochloride

Step 1: To a solution of 2,2-dimethyl-2H-1,4-benzoxazin-3(4H)-one⁴(2.658 g, 15.0 mmol) in tetrahydrofuran (10 mL) under nitrogen was addedslowly a solution of borane (1.0 M in tetrahydrofuran, 22.5 mL, 22.5mmol) via a syringe. The resulting mixture was stirred at roomtemperature for 10 minutes and then at 70° C. for 1 hour. After cooling,the reaction mixture was quenched with methanol (3 mL) slowly. Allvolatiles were removed under reduced pressure. A 1 N aqueous solution ofhydrochloric acid (10 mL) was added to the liquid residue and themixture was warmed to 50° C. for 10 minutes. After cooling, the reactionmixture was made alkaline using saturated sodium bicarbonate solution(15 mL), and extracted with ethyl acetate (25 mL). The organic layer waswashed with water, brine, dried (anhydrous sodium sulfate), filteredthrough a pad of silica gel, and concentrated under reduced pressure toyield 2.310 g (94%) of 2,2-dimethyl-3,4-dihydro-2H-1,4-benzoxazine as abrown oil. MS (ES) m/z 164.0 ([M+H]⁺). ⁴Caliendo, G.; Perissutti, E.;Santagada, V.; Fiorino, F.; Severino, B.; Bianca, R.

Step 2: In an analogous manner to EXAMPLE 6, step 4,(2S,3S)-3-(2,2-dimethyl-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-3-(3-fluorophenyl)propane-1,2-diolwas prepared from 2,2-dimethyl-3,4-dihydro-2H-1,4-benzoxazine and[(2R,3R)-3-(3-fluorophenyl)oxiran-2-yl]methanol (EXAMPLE 6, step 3) as awhite solid. MS (ES) m/z 332.2 ([M+H]⁺); HRMS: calcd for C₁₉H₂₂FNO₃+H⁺,332.1657; found (ESI, [M+H]⁺), 332.1648.

Step 3: In an analogous manner to EXAMPLE 6, step 6,(1S,2R)-1-(2,2-dimethyl-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-1-(3-fluorophenyl)-3-(methylamino)propan-2-olhydrochloride was prepared from(2S,3S)-3-(2,2-dimethyl-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-3-(3-fluorophenyl)propane-1,2-diolas a white powder. MS (ES) m/z 345.2 ([M+H]⁺); HRMS: calcd forC₂₀H₂₅FN₂O₂+H⁺, 345.1978; found (ESI, [M+H]⁺), 345.1981.

Example 17(1S,2R)-1-(2,2-dimethyl-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-3-(methylamino)-1-phenylpropan-2-olhydrochloride

In an analogous manner to EXAMPLE 6, step 4,(2S,3S)-3-(2,2-dimethyl-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-3-phenylpropane-1,2-diolwas prepared from 2,2-dimethyl-3,4-dihydro-2H-1,4-benzoxazine (EXAMPLE16, step 1) and [(2R,3R)-3-phenyloxiran-2-yl]methanol (EXAMPLE 10, step4) as a white solid. MS (ES) m/z 314.1 ([M+H]⁺).

In an analogous manner to EXAMPLE 6, step 6,(1S,2R)-1-(2,2-dimethyl-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-3-(methylamino)-1-phenylpropan-2-olhydrochloride was prepared from(2S,3S)-3-(2,2-dimethyl-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-3-phenylpropane-1,2-diolas a white powder. MS (ES) m/z 327.2 ([M+H]⁺); HRMS: calcd forC₂₀H₂₆N₂O₂+H⁺, 327.2073; found (ESI, [M+H]⁺), 327.2082.

Example 18(1S,2R)-1-(2,3-dihydro-4H-1,4-benzothiazin-4-yl)-1-(3-fluorophenyl)-3-(methylamino)propan-2-olhydrochloride

In an analogous manner to EXAMPLE 6, step 4,(2S,3S)-3-(2,3-dihydro-4H-1,4-benzothiazin-4-yl)-3-(3-fluorophenyl)propane-1,2-diolwas prepared from 3,4-dihydro-2H-1,4-benzothiazine⁵ and[(2R,3R)-3-(3-fluorophenyl)oxiran-2-yl]methanol (EXAMPLE 6, step 3) as aviscous, yellowish liquid. MS (ES) m/z 320.1 ([M+H]⁺); HRMS: calcd forC₁₇H₁₈FN02S+H⁺, 320.1115; found (ESI, [M+H]⁺), 320.1113. ⁵El-Subbagh, H.I.; Abadi, A. H.; Al-Khawad, I. E.; Al-Rashood, K. A. Arch. Pharm. 1999,332, 19-24.

In an analogous manner to EXAMPLE 6, step 6,(1S,2R)-1-(2,3-dihydro-4H-1,4-benzothiazin-4-yl)-1-(3-fluorophenyl)-3-(methylamino)propan-2-olhydrochloride was prepared from(2S,3S)-3-(2,3-dihydro-4H-1,4-benzothiazin-4-yl)-3-(3-fluorophenyl)propane-1,2-diolas a white powder. MS (ES) m/z 333.1 ([M+H]⁺); HRMS: calcd forC₁₈H₂₁FN₂OS+H⁺, 333.1431; found (ESI, [M+H]⁺), 333.1420.

Example 19(1S,2R)-1-(3-fluorophenyl)-3-(methylamino)-1-(2-phenyl-2,3-dihydro-4H-1,4-benzoxazin-4-yl)propan-2-olhydrochloride

In an analogous manner to EXAMPLE 6, step 4,(2S,3S)-3-(3-fluorophenyl)-3-(2-phenyl-2,3-dihydro-4H-1,4-benzoxazin-4-yl)propane-1,2-diolwas prepared from 2-phenyl-3,4-dihydro-2H-1,4-benzoxazine⁶ and[(2R,3R)-3-(3-fluorophenyl)oxiran-2-yl]methanol (EXAMPLE 6, step 3) as awhite solid. MS (ES) m/z 380.0 ([M+H]⁺); HRMS: calcd for C₂₃H₂₂FNO₃+H⁺,380.1662; found (ESI, [M+H]⁺), 380.1661. ⁶Olagbemiro, T. O.; Nyakutse,C. A.; Lajide, L.; Agho, M. O.; Chukwu, C. E. Bull. Soc. Chim. Belg.1987, 96, 473-480.

In an analogous manner to EXAMPLE 6, step 6,(1S,2R)-1-(3-fluorophenyl)-3-(methylamino)-1-(2-phenyl-2,3-dihydro-4H-1,4-benzoxazin-4-yl)propan-2-olhydrochloride was prepared from(2S,3S)-3-(3-fluorophenyl)-3-(2-phenyl-2,3-dihydro-4H-1,4-benzoxazin-4-yl)propane-1,2-diolas a white powder. MS (ES) m/z 393.2 ([M+H]⁺); HRMS: calcd forC₂₄H₂₅FN₂O₂+H⁺, 393.1978; found (ESI, [M+H]⁺), 393.1986.

Example 20(1S,2R)-1-(3-fluorophenyl)-3-(methylamino)-1-[(2R)-2-phenyl-2,3-dihydro-4H-1,4-benzoxazin-4-yl]propan-2-olhydrochloride

Step 1: Diastereomeric mixture of(1S,2R)-1-(3-fluorophenyl)-3-(methylamino)-1-(2-phenyl-2,3-dihydro-4H-1,4-benzoxazin-4-yl)propan-2-ol(EXAMPLE 19) was dissolved in methanol. The resulting solution wasinjected onto the Supercritical Fluid Chromatography instrument. Thebaseline resolved diastereomers, using the conditions described below,were collected.

SFC Instrument: Berger MultiGram Prep SFC (Berger Instruments, Inc.Newark, DE 19702. Column: Ethyl pyridine; 250 mm L × 20 mm ID (PrincetonChromatography Inc.) Column temperature: 35° C. SFC Modifier: 15% MeOHwith 85% CO₂ Flow rate: 50 mL/min Outlet Pressure: 100 bar Detector: UVat 220 nm

Step 2:(1S,2R)-1-(3-fluorophenyl)-3-(methylamino)-1-[(2R)-2-phenyl-2,3-dihydro-4H-1,4-benzoxazin-4-yl]propan-2-ol,isolated as peak 1, was subjected to hydrochloride salt formation in ananalogous manner to EXAMPLE 13, step 2 to give(1S,2R)-1-(3-fluorophenyl)-3-(methylamino)-1-[(2R)-2-phenyl-2,3-dihydro-4H-1,4-benzoxazin-4-yl]propan-2-olhydrochloride as a white powder. MS (ES) m/z 393.2 ([M+H]⁺); HRMS: calcdfor C₂₄H₂₅FN₂O₂+H⁺, 393.1973; found (ESI, [M+H]⁺), 393.1992.

Example 21(1S,2R)-1-(3-fluorophenyl)-3-(methylamino)-1-[(2S)-2-phenyl-2,3-dihydro-4H-1,4-benzoxazin-4-yl]propan-2-olhydrochloride

In an analogous manner to EXAMPLE 20,(1S,2R)-1-(3-fluorophenyl)-3-(methylamino)-1-[(2S)-2-phenyl-2,3-dihydro-4H-1,4-benzoxazin-4-yl]propan-2-olhydrochloride was prepared as a white powder from(1S,2R)-1-(3-fluorophenyl)-3-(methylamino)-1-[(2S)-2-phenyl-2,3-dihydro-4H-1,4-benzoxazin-4-yl]propan-2-ol,which was isolated as peak 2 of the diastereomeric separation (EXAMPLE20, step 1). MS (ES) m/z 393.2 ([M+H]⁺); HRMS: calcd for C₂₄H₂₅FN₂O₂+H⁺,393.1973; found (ESI, [M+H]⁺), 393.1982.

Cell Lines, Culture Reagents, and Assays

MDCK-Net6 cells, stably transfected with human hNET (Pacholczyk, T., R.D. Blakely, and S. G. Amara, Nature, 1991, 350(6316): p. 350-4) werecultured in growth medium containing high glucose DMEM (Gibco, Cat. No.11995), 10% FBS (dialyzed, heat-inactivated, US Bio-Technologies, LotFBD1129HI) and 500 □g/ml G418 (Gibco, Cat. No. 10131). Cells were platedat 300,000/T75 flask and cells were split twice weekly. The JAR cellline (human placental choriocarcinoma) was purchased from ATCC (Cat. No.HTB-144). The cells were cultured in growth medium containing RPMI 1640(Gibco, Cat. No. 72400), 10% FBS (Irvine, Cat. No. 3000), 1% sodiumpyruvate (Gibco, Cat. No. 1136) and 0.25% glucose. Cells were plated at250,000 cells/T75 flask and split twice weekly. For all assays, cellswere plated in Wallac 96-well sterile plates (PerkinElmer, Cat. No.3983498).

Norepinephrine (NE) Uptake Assay

On day 1, cells were plated at 3,000 cells/well in growth medium andmaintained in a cell incubator (37° C., 5% CO₂). On day 2, growth mediumwas replaced with 200 μl of assay buffer (25 mM HEPES; 120 mM NaCl; 5 mMKCl; 2.5 mM CaCl₂; 1.2 mM MgSO₄; 2 mg/ml glucose (pH 7.4, 37° C.))containing 0.2 mg/ml ascorbic acid and 10 μM pargyline. Platescontaining cells with 200 μl of assay buffer were equilibrated for 10minutes at 37° C. prior to addition of compounds. A stock solution ofdesipramine was prepared in DMSO (10 mM) and delivered to triplicatewells containing cells for a final test concentration of 1 μM. Data fromthese wells were used to define non-specific NE uptake (minimum NEuptake). Test compounds were prepared in DMSO (10 mM) and diluted inassay buffer according to test range (1 to 10,000 nM). Twenty-fivemicroliters of assay buffer (maximum NE uptake) or test compound wereadded directly to triplicate wells containing cells in 200 μl of assaybuffer. The cells in assay buffer with test compounds were incubated for20 minutes at 37° C. To initiate the NE uptake, [³H]NE diluted in assaybuffer (120 nM final assay concentration) was delivered in 25 μlaliquots to each well and the plates were incubated for 5 minutes (37°C.). The reaction was terminated by decanting the supernatant from theplate. The plates containing cells were washed twice with 200 μl assaybuffer (37° C.) to remove free radioligand. The plates were theninverted, left to dry for 2 minutes, then reinverted and air-dried foran additional 10 minutes. The cells were lysed in 25 μl of 0.25 N NaOHsolution (4° C.), placed on a shake table and vigorously shaken for 5minutes. After cell lysis, 75 μl of scintillation cocktail was added toeach well and the plates were sealed with film tape. The plates werereturned to the shake table and vigorously shaken for a minimum of 10minutes to ensure adequate partitioning of organic and aqueoussolutions. The plates were counted in a Wallac Microbeta counter(PerkinElmer) to collect the raw cpm data.

Serotonin (5-HT) Uptake Assay

The methods for 5-HT functional reuptake using the JAR cell line weremodified using a previous literature report (Prasad, et al., Placenta,1996. 17(4): 201-7). On day 1, cells were plated at 15,000 cells/well in96-well plates containing growth medium (RPMI 1640 with 10% FBS) andmaintained in a cell incubator (37° C., 5% CO₂). On day 2, cells werestimulated with staurosporine (40 nM) to increase the expression of the5-HT transporter [17]. On day 3, cells were removed from the cellincubator two hours prior to assay and maintained at room temperature toequilibrate the growth medium to ambient oxygen concentration.Subsequently, the growth medium was replaced with 200 μl of assay buffer(25 mM HEPES; 120 mM NaCl; 5 mM KCl; 2.5 mM CaCl₂; 1.2 mM MgSO₄; 2 mg/mlglucose (pH 7.4, 37° C.)) containing 0.2 mg/ml ascorbic acid and 10 μMpargyline. A stock solution of paroxetine (AHR-4389-1) was prepared inDMSO (10 mM) and delivered to triplicate wells containing cells for afinal test concentration of 1 μM. Data from these wells were used todefine non-specific 5-HT uptake (minimum 5-HT uptake). Test compoundswere prepared in DMSO (10 mM) and diluted in assay buffer according totest range (1 to 1,000 nM). Twenty-five microliters of assay buffer(maximum 5-HT uptake) or test compound were added directly to triplicatewells containing cells in 200 μl of assay buffer. The cells wereincubated with the compound for 10 minutes (37° C.). To initiate thereaction, [³H]hydroxytryptamine creatinine sulfate diluted in assaybuffer was delivered in 25 μl aliquots to each well for a final testconcentration of 15 nM. The cells were incubated with the reactionmixture for 5 minutes at 37° C. The 5-HT uptake reaction was terminatedby decanting the assay buffer. The cells were washed twice with 200 μlassay buffer (37° C.) to remove free radioligand. The plates wereinverted and left to dry for 2 minutes, then reinverted and air-driedfor an additional 10 minutes. Subsequently, the cells were lysed in 25μl of 0.25 N NaOH (4° C.) then placed on a shaker table and shakenvigorously for 5 minutes. After cell lysis, 75 μl of scintillationcocktail was added to the wells, the plates were sealed with film tapeand replaced on the shake table for a minimum of 10 minutes. The plateswere counted in a Wallac Microbeta counter (PerkinElmer) to collect theraw cpm data.

Evaluation of Results

For each experiment, a data stream of cpm values collected from theWallac Microbeta counter was downloaded to a Microsoft Excel statisticalapplication program. Calculations of EC₅₀ values were made using thetransformed-both-sides logistic dose response program written by WyethBiometrics Department. The statistical program uses mean cpm values fromwells representing maximum binding or uptake (assay buffer) and mean cpmvalues from wells representing minimum binding or uptake ((1 μMdesipramine (hNET) or 1 μM paroxetine (hSERT)). Estimation of the EC₅₀value was completed on a log scale and the line was fit between themaximum and minimum binding or uptake values. All graphic datarepresentation was generated by normalizing each data point to a meanpercent based on the maximum and minimum binding or uptake values. TheEC₅₀ values reported from multiple experiments were calculated bypooling the raw data from each experiment and analyzing the pooled dataas one experiment. The results are reported in Table 1.

TABLE 1 Example % Inhibition @ 1 μM (hNET) 2 33.7 4 46.2 5 52.9 8 12.5 953.9 11 60.6 12 3.4 13 38.6 14 41.5 15 41.4 16 10 17 9.3 18 90.4 19 9520 97.2 21 51.7

When ranges are used herein for physical properties, such as molecularweight, or chemical properties, such as chemical formulae, allcombinations and subcombinations of ranges specific embodiments thereinare intended to be included.

The disclosures of each patent, patent application and publication citedor described in this document are hereby incorporated herein byreference, in its entirety.

Those skilled in the art will appreciate that numerous changes andmodifications can be made to the preferred embodiments of the inventionand that such changes and modifications can be made without departingfrom the spirit of the invention. It is, therefore, intended that theappended claims cover all such equivalent variations as fall within thetrue spirit and scope of the invention.

1. A compound of formula I:

or a pharmaceutically acceptable salt thereof; wherein: the dotted linerepresents an optional double bond between U and V or V and W; U is,independently, S, SO, SO₂, C═O, N, NR₃, or C(R₈)₂; W is CH, CH₂, or C═O;provided that when W is CH₂, U is not C(R₈)₂; V is C(R₈), C(R₈)₂, O, orN(R₈); R₁ is, independently at each occurrence, alkyl, alkoxy, halo,CF₃, OCF₃, arylalkyloxy substituted with 0-3 R₉, aryloxy substitutedwith 0-3 R₉, aryl substituted with 0-3 R₉, heteroaryl substituted with0-3 R₉, hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, alkynyl,alkylsulfoxide, phenylsulfoxide substituted with 0-3 R₉, alkylsulfone,phenylsulfone substituted with 0-3 R₉, alkylsulfonamide,phenylsulfonamide substituted with 0-3 R₉, heteroaryloxy substitutedwith 0-3 R₉, heteroarylmethyloxy substituted with 0-3 R₉, alkylamido, orphenylamido substituted with 0-3 R₉; or two adjacent R₁ also representmethylenedioxy; R₂ is aryl substituted with 0-3 R₁ or heteroarylsubstituted with 0-3 R₁; R₃ is H, C₁-C₄ alkyl substituted with 0-3 R₁,C₃-C₆ cycloalkyl, or phenyl substituted with 0-3 R₁; R₄ is,independently at each occurrence, H, C₁-C₄ alkyl, arylalkyl,heteroarylmethyl, cycloheptylmethyl, cyclohexylmethyl,cyclopentylmethyl, or cyclobutylmethyl, or both R₄ groups, together withthe nitrogen through which they are attached, form a heterocyclic ringof 4 to 6 ring atoms, where one carbon may be optionally replaced withN, O, S, or SO₂, and where any carbon ring atom or additional N atom maybe optionally substituted with C₁-C₄ alkyl, F, or CF₃; R₅ is H or C₁-C₄alkyl; R₆ is H or C₁-C₄ alkyl; R₇ is, independently at each occurrence,H, or C₁-C₄ alkyl, or R₇ and R₄ together with the nitrogen to which R₄is attached form a nitrogen-containing ring containing 3-6 carbon atoms;R₈ is, independently at each occurrence, H, C₁-C₄ alkyl, C₃-C₆heteroalkyl, or aryl substituted with 0-3 R₁; R₉ is, independently ateach occurrence, alkyl, alkoxy, halo, CF₃, OCF₃, hydroxy, alkanoyloxy,nitro, nitrile, alkenyl, alkynyl, alkylsulfoxide, alkylsulfone,alkylsulfonamide, or alkylamido; or two adjacent R₉ also representmethylenedioxy; n is an integer from 0 to 4; x is an integer from 1 to2; and wherein 1-3 carbon atoms in ring A may optionally be replacedwith N.
 2. (canceled)
 3. A compound according to claim 1, wherein: W isCH₂.
 4. A compound according to claim 1, wherein: R₁ is halo.
 5. Acompound according to claim 4, wherein: R₁ is fluoro or chloro.
 6. Acompound according to claim 1, wherein: R₂ is aryl substituted with 0-3R₁.
 7. A compound according to claim 6, wherein: aryl is phenyl.
 8. Acompound according to claim 1, wherein: R₃ is H or C₁ alkyl.
 9. Acompound according to claim 1, wherein: R₄ is H or C₁-C₄ alkyl.
 10. Acompound according to claim 9, wherein: R₄ is H, methyl, ethyl, orisopropyl.
 11. A compound according to claim 1, wherein: both R₄ groups,together with the nitrogen through which they are attached, form apyridine, piperidine, piperazine, or morpholine ring.
 12. A compoundaccording to claim 1, wherein: R₅ is, independently at each occurrence,H or C₁ alkyl.
 13. A compound according to claim 1, wherein: n is 0or
 1. 14. A compound according to claim 1, which is one of thefollowing:3-(methylamino)-1-(4-methyl-3,4-dihydroquinoxalin-1(2H)-yl)-1-phenylpropan-2-ol;3-(methylamino)-1-phenyl-1-[4-(2,2,2-trifluoroethyl)-3,4-dihydroquinoxalin-1(2H)-yl]propan-2-ol;1-(2,3-dihydro-4H-1,4-benzothiazin-4-yl)-1-(3-fluorophenyl)-3-(methylamino)propan-2-ol;1-(3-fluorophenyl)-3-(methylamino)-1′-[2-phenyl-2,3-dihydro-4H-1,4-benzoxazin-4-yl]propan-2-ol;or1-(3-fluorophenyl)-3-(methylamino)-1-[2-phenyl-2,3-dihydro-4H-1,4-benzoxazin-4-yl]propan-2-ol;or a pharmaceutically acceptable salt thereof.
 15. A compound accordingto claim 1, which is one of the following:(1S*,2R*)-3-(methylamino)-1-(4-methyl-3,4-dihydroquinoxalin-1(2H)-yl)-1-phenylpropan-2-ol;(1S*,2R*)-3-(methylamino)-1-phenyl-1-[4-(2,2,2-trifluoroethyl)-3,4-dihydroquinoxalin-1(2H)-yl]propan-2-ol;(1S,2R)-1-(2,3-dihydro-4H-1,4-benzothiazin-4-yl)-1-(3-fluorophenyl)-3-(methylamino)propan-2-ol;a pharmaceutically acceptable salt thereof.
 16. A composition,comprising: a. at least one compound according to claim 1; and b. atleast one pharmaceutically acceptable carrier.
 17. A method for treatingor preventing a condition ameliorated by monoamine reuptake in a subjectin need thereof, comprising the step of: administering to said subjectan effective amount of a compound according to claim 1 orpharmaceutically acceptable salt thereof.
 18. A method according toclaim 17, wherein said condition ameliorated by monoamine reuptake isselected from the group consisting of vasomotor symptoms, sexualdysfunction, gastrointestinal and genitourinary disorders, chronicfatigue syndrome, fibromyalgia syndrome, nervous system disorders, andcombinations thereof.
 19. A method according to claim 18, wherein saidcondition ameliorated by monoamine reuptake is selected from the groupconsisting of major depressive disorder, vasomotor symptoms, stress andurge urinary incontinence, fibromyalgia, pain, diabetic neuropathy, andcombinations thereof.
 20. A method for treating or preventing at leastone vasomotor symptom in a subject in need thereof, comprising the stepof: administering to said subject an effective amount of a compoundaccording to claim 1 or pharmaceutically acceptable salt thereof.
 21. Amethod according to claim 20, wherein said vasomotor symptom is hotflush.
 22. A method according to claim 21, wherein said subject ishuman.
 23. A method according to claim 22, wherein said human is afemale.
 24. A method according to claim 23, wherein said female ispre-menopausal.
 25. A method according to claim 23, wherein said femaleis peri-menopausal.
 26. A method according to claim 23, wherein saidfemale is post-menopausal.
 27. A method according to claim 22, whereinsaid human is a male.
 28. A method according to claim 27, wherein saidmale is naturally, chemically or surgically andropausal.
 29. A methodfor treating or preventing at least one depression disorder in a subjectin need thereof, comprising the step of: administering to said subjectan effective amount of a compound according to claim 1 orpharmaceutically acceptable salt thereof.
 30. A method according toclaim 29, wherein said depression disorder is major depressive disorder,anxiety, sleep disturbance, or social phobia.
 31. A method according toclaim 30, wherein said subject is human.
 32. A method for treating orpreventing at least one sexual dysfunction in a subject in need thereof,comprising the step of: administering to said subject an effectiveamount of a compound according to claim 1 or pharmaceutically acceptablesalt thereof.
 33. A method according to claim 32, wherein said sexualdysfunction is desire-related or arousal-related.
 34. A method accordingto claim 33, wherein said subject is human.
 35. A method for treating orpreventing pain in a subject in need thereof, comprising the step of:administering to said subject an effective amount of a compoundaccording to claim 1 or pharmaceutically acceptable salt thereof.
 36. Amethod according to claim 35, wherein said pain is acute centralizedpain, acute peripheral pain, or a combination thereof.
 37. A methodaccording to claim 35, wherein said pain is chronic centralized pain,chronic peripheral pain, or a combination thereof.
 38. A methodaccording to claim 35, wherein said pain is neuropathic pain, visceralpain, musculoskeletal pain, bony pain, cancer pain, inflammatory pain,or a combination thereof.
 39. A method according to claim 38, whereinsaid neuropathic pain is associated with diabetes, post traumatic painof amputation, lower back pain, cancer, chemical injury, toxins, majorsurgery, peripheral nerve damage due to traumatic injury compression,post-herpetic neuralgia, trigeminal neuralgia, lumbar or cervicalradiculopathies, fibromyalgia, glossopharyngeal neuralgia, reflexsympathetic dystrophy, casualgia, thalamic syndrome, nerve rootavulsion, reflex sympathetic dystrophy or post thoracotomy pain,nutritional deficiencies, viral infection, bacterial infection,metastatic infiltration, adiposis dolorosa, burns, central painconditions related to thalamic conditions, and combinations thereof. 40.A method according to claim 38, wherein said visceral pain is associatedwith ulcerative colitis, irritable bowel syndrome, irritable bladder,Crohn's disease, rheumatologic (arthralgias), tumors, gastritis,pancreatitis, infections of the organs, biliary tract disorders, andcombinations thereof.
 41. A method according to claim 35, wherein saidpain is female-specific pain.
 42. A method according to claim 35,wherein said subject is human.
 43. A method for treating or preventinggastrointestinal or genitourinary disorder in a subject in need thereof,comprising the step of: administering to said subject an effectiveamount of a compound according to claim 1 or pharmaceutically acceptablesalt thereof.
 44. A method according to claim 43, wherein said disorderis stress incontinence or urge urinary incontinence.
 45. A methodaccording to claim 44, wherein said subject is human.
 46. A method fortreating or preventing chronic fatigue syndrome in a subject in needthereof, comprising the step of: administering to said subject aneffective amount of a compound according to claim 1 or pharmaceuticallyacceptable salt thereof.
 47. A method according to claim 46, whereinsaid subject is human.
 48. A method for treating or preventingfibromyalgia syndrome in a subject in need thereof, comprising the stepof: administering to said subject an effective amount of a compoundaccording to claim 1 or pharmaceutically acceptable salt thereof.
 49. Amethod according to claim 48, wherein said subject is human.